Pro-Neurogenic Compounds

ABSTRACT

Compounds and methods for stimulating neurogenesis (e.g., post-natal neurogenesis, including post-natal hippocampal and hypothalamic neurogenesis) and/or protecting neuronal cell from cell death are disclosed herein. In vivo activity tests suggest that these compounds may have therapeutic benefits in neuropsychiatric and/or neurodegenerative diseases such as schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic stress disorder, Parkinson&#39;s disease, Alzheimer&#39;s disease, Down syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington&#39;s disease, stroke, radiation therapy, chronic stress, abuse of a neuro-active drug, retinal degeneration, spinal cord injury, peripheral nerve injury, physiological weight loss associated with various conditions, as well as cognitive decline associated with normal aging, chemotherapy, and the like.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of U.S. ProvisionalApplication No. 61/693,108 filed Aug. 24, 2012, the entire content ofwhich application is hereby incorporated herein by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with government support under Grant Numbers5DPlOD00027605, 5R37MH05938809, and 1RO1MH087986, which were awarded bythe National Institute of Health; the Government has certain rights inthe invention.

TECHNICAL FIELD

This presently disclosed embodiments relate generally to the discoveryof pro-neurogenic compounds capable of promoting neurogenesis and/orreducing neuronal cell death.

BACKGROUND

It is now accepted that the adult vertebrate brain fosters the birth andfunctional incorporation of newly formed neurons (Goldman and Nottebohm,Proc Natl Acad Sci USA 1983, 80: 2390-2394; Paton and Nottebohm, Science1984, 225, 1046-1048; Burd and Nottebohm, J Comp Neurol 1985,240:143-152). However, it was long thought that no new neurons could beadded to the adult mammalian brain. This dogma was challenged in the1960's when autoradiographic evidence of new neuron formation in thehippocampal dentate gyms, olfactory bulb, and cerebral cortex of theadult rat was presented (Altman, J. Science 1962, 135, 1127-1128;Altman, J. J Comp Neurol 1966, 128:431-474; Altman, Anat Rec 1963,145:573-591; Altman and Das, J. Comp. Neurol. 1965, 124, 319-335; Altmanand Das, J Comp Neurol 1966, 126:337-390). It is now accepted thatwithin all mammalian species, including humans (Eriksson et al., Nat.Med. 1998, 4(11), 1313-1317), there are two major reservoirs of neuronalstem cells, one located in the subgranular zone (SGZ) of the hippocampaldentate gyms and another in the subventricular zone (SVZ) (Gross, Natl.Rev. 2000, 1, 67-72). Neural stem cells in the SVZ facilitate formationof new neurons that migrate rostrally to populate the olfactory bulb,while neural stem cells in the SGZ produce neurons that integratelocally in the granular layer of the dentate gyrus, a region of thehippocampus that exhibits lifelong structural and functional plasticity.

The process of new neuron formation in the adult mouse brain can beinfluenced by environmental, chemical and genetic variables. Asdemonstrated by Gage and colleagues, neurogenesis in the adult mousebrain is enhanced when animals are exposed to an enriched environment(Kempermann et al., Nature 1997, 386, 493-495) or able to exercisevoluntarily (van Praag et al., Nat. Neuro-sci. 1999, 2, 266-270). Morerecently, anti-depressant drugs have been shown to enhance levels ofadult neurogenesis in animals, including humans (Schmidt et al., BehavPharmacol. 2007 September; 18(5-6):391-418; Boldrini et al.,Neuropsychopharmacology 2009, 34, 2376-2389). Among many genes reportedto impact adult neurogenesis is the gene encoding neuronal PAS domainprotein 3 (NPAS3), a central nervous system (CNS)-specific transcriptionfactor that has been associated with schizophrenia and bipolar disorder(Kamnasaran et al., J. Med. Genet. 2003, 40, 325-332; Pickard et al.,Am. J. Med. Genet. B. Neuropsychiatr. Genet. 2005, 136B, 26-32; Pickardet al., Ann Med. 2006, 38, 439-448; Pickard et al., Mol. Psychiatry.2009, 14, 874-884; Lavedan et al., Pharmacogenomics 2008, 9: 289-301)Animals missing both copies of the NPAS3 gene suffer a profound loss ofadult hippocampal neurogenesis coupled with significant behavioraldeficits (Pieper et al., Proc. Natl. Acad. Sci. USA 2005, 102,14052-14057). Knowing that impaired post-natal neurogenesis elicitsunfavorable phenotypic deficits, it is predicted that pro-neurogenicchemical compounds should exhibit favorable therapeutic benefits.

SUMMARY

The presently disclosed embodiments relate generally to compounds thatpromote the generation or the survival of existing neurons in themammalian brain. For the purpose of simplicity these compounds arereferred to as being pro-neurogenic. In certain embodiments, thecompounds promote the generation or survival of neurons in thepost-natal mammalian brain. In certain embodiments, the compoundspromote the survival, growth, development and/or function of neurons,particularly CNS, brain, cerebral, and hippocampal neurons. In certainembodiments, the compounds stimulate post-natal hippocampalneurogenesis, which while not wishing to be bound by theory, is believedto represent a therapeutic target for a variety of neuropsychiatric andneurodegenerative diseases, including (but not limited to)schizophrenia, major depression, bipolar disorder, normal aging,epilepsy, traumatic brain injury, post-traumatic stress disorder,Parkinson's disease, Alzheimer's disease, Down syndrome, spinocerebellarataxia, amyotrophic lateral sclerosis, Huntington's disease, stroke,radiation therapy, chronic stress, abuse of neuro-active drugs (such asalcohol, opiates, methamphetamine, phencyclidine, and cocaine), retinaldegeneration, spinal cord injury, and peripheral nerve injury. Incertain embodiments, the compounds stimulate post-natal hypothalamicneurogenesis, which can provide therapeutic benefits in weightmanagement, such as physiological weight loss associated with variousconditions, including but not limited to, normal aging, chemotherapy,radiation therapy, stress, drug abuse, anorexia, as well as otherdiseases discussed herein.

In an aspect, compounds of the presently disclosed embodiments mayinclude those represented by formula (I):

wherein:

-   -   R² and R³, together with C1 and C2, form the optionally        substituted phenyl, pyridine or pyrimidine ring of formulas        (II)-(IV) described below, or are defined as R^(2d) and R^(3d)        of formula (V), respectively;    -   R⁴ is defined as any one of R^(4a)-R^(4d) in formulas (II)-(IV);        and    -   n is 0 or 2.

For example, a compound or pharmaceutically acceptable salt thereof, forpromoting neurogenesis and/or reducing neuronal cell death, can berepresented by formula (II):

-   -   wherein R^(1a) is selected from the group consisting of:        —CH₂—C(O)—Z^(1a) and —CH₂—C(R^(A1))(R^(A2))—CH₂—Z^(2a); and    -   R^(3a) and R^(4a) are each independently selected from the group        consisting of: hydrogen, halo, hydroxyl, C₁₋₃ alkoxyl, cyano,        carboxyl, and formamide;        -   wherein Z^(1a) is selected from the group consisting of:            hydroxyl; C₁₋₆ alkoxyl; amine optionally substituted with 1            or more C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₃₋₁₂ cycloalkyl, C₁₋₁₂            sulfonyl optionally substituted with 1-6 halo, C₆₋₁₂ aryl            sulfonyl optionally substituted with 1-6 halo, C₄₋₁₂            heteroaryl sulfonyl optionally substituted with 1-6 halo,            C₂₋₁₂ carbonyl optionally substituted with 1-6 halo, and/or            C₂₋₁₂ carboxyalkyl optionally substituted with 1-6 halo;            C₂₋₁₂ heterocyclyl; C₆₋₁₂ aryl optionally substituted with 1            or more halo, hydroxyl, C₁₋₆ alkyl and/or C₁₋₆ alkoxyl; and            C₄₋₁₂ heteroaryl optionally substituted with 1 or more halo,            hydroxyl, C₁₋₆ alkyl and/or C₁₋₆ alkoxyl;        -   wherein one of R^(A1) and R^(A2) is hydroxyl, halo, or amine            optionally substituted with 1 or more C₁₋₆ alkyl, C₂₋₆            alkenyl, C₃₋₆ cycloalkyl, C₂₋₆ heterocyclyl, C₆₋₁₂ aryl,            and/or C₄₋₁₂ heteroaryl; and the other of R^(A1) and R^(A2)            is hydrogen;        -   wherein Z^(2a) is selected from the group consisting of:            halo, O(R^(a)), S(R^(b)) and N(R^(c))(R^(d));        -   wherein R^(a) and R^(b) are each independently selected from            the group consisting of: C₁₋₁₂ alkyl; C₂₋₁₂ alkenyl; C₃₋₁₂            cycloalkyl; C₂₋₆ heterocyclyl; C₆₋₁₂ aryl optionally            substituted with 1 or more halo, hydroxyl, C₁₋₆ alkyl and/or            C₁₋₆ alkoxyl; and C₄₋₁₂ heteroaryl optionally substituted            with 1 or more halo, hydroxyl, C₁₋₆ alkyl and/or C₁₋₆            alkoxyl;        -   wherein R^(c) and R^(d) are each independently selected from            the group consisting of: hydrogen; C₁₋₁₂ alkyl; C₂₋₁₂            alkenyl; C₃₋₁₂ cycloalkyl; C₂₋₆ heterocyclyl; C₆₋₁₂ aryl            optionally substituted with 1 or more halo, hydroxyl, C₁₋₆            alkyl and/or C₁₋₆ alkoxyl; and C₄₋₁₂ heteroaryl optionally            substituted with 1 or more halo, hydroxyl, C₁₋₆ alkyl and/or            C₁₋₆ alkoxyl; or wherein R^(c) and R^(d) together with the            nitrogen they are attached to form a C₄₋₁₄ heteroaryl            optionally substituted with 1 or more halo, hydroxyl, C₁₋₆            alkyl and/or C₁₋₆ alkoxyl.

In some embodiments, one or more of the following definitions apply:

-   (1) R^(3a) and R^(4a) are both hydrogen or both bromo;-   (2) Z^(1a) is hydroxyl or amine optionally substituted with 1 or    more C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, and/or C₃₋₁₂ cycloalkyl;-   (3) one of R^(A1) and R^(A2) is hydroxyl or halo; and the other of    R^(A1) and R^(A2) is hydrogen;-   (4) Z^(2a) is O(R^(a)) or S(R^(b)); and/or-   (5) Z^(2a) is N(R^(c))(R^(d)).

For example, R^(1a) may be —CH₂—C(O)—Z^(1a) or—CH₂—C(R^(A1))(R^(A2))—CH₂—Z^(2a).

When R^(1a) is —CH₂—C(O)—Z^(1a), Z^(1a) may be hydroxyl or C₁₋₆ alkoxyl.Z^(1a) may also be amine optionally substituted with 1 or more C₁₋₁₂alkyl, C₂₋₁₂ alkenyl, C₃₋₁₂ cycloalkyl, C₁₋₁₂ sulfonyl optionallysubstituted with 1-6 halo, C₆₋₁₂ aryl sulfonyl optionally substitutedwith 1-6 halo, C₄₋₁₂ heteroaryl sulfonyl optionally substituted with 1-6halo, C₂₋₁₂ carbonyl optionally substituted with 1-6 halo, and/or C₂₋₁₂carboxyalkyl optionally substituted with 1-6 halo. For example, Z^(1a)can be amine optionally substituted with 1 or more C₁₋₁₂ alkyl, C₂₋₁₂alkenyl, and/or C₃₋₁₂ cycloalkyl. Z^(1a) may also be C₂₋₁₂ heterocyclyl;C₆₋₁₂ aryl optionally substituted with 1 or more halo, hydroxyl, C₁₋₆alkyl and/or C₁₋₆ alkoxyl; or C₄₋₁₂ heteroaryl optionally substitutedwith 1 or more halo, hydroxyl, C₁₋₆ alkyl and/or C₁₋₆ alkoxyl.

When R^(1a) is —CH₂—C(R^(A1))(R^(A2))—CH₂—Z^(2a), both of R^(A1) andR^(A2) can be hydrogen. Alternatively, one of R^(A1) and R^(A2) ishydroxyl, halo (e.g., fluoro), or amine optionally substituted with 1 ormore C₁₋₆ alkyl (e.g., methyl), C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₂₋₆heterocyclyl, C₆₋₁₂ aryl, and/or C₄₋₁₂ heteroaryl; and the other ofR^(A1) and R^(A2) is hydrogen. Z^(2a) can be halo, O(R^(a)), S(R^(b)) orN(R^(c))(R^(d)). R^(a) and R^(b) are each common substitutients such as:C₁₋₁₂ alkyl; C₂₋₁₂ alkenyl; C₃₋₁₂ cycloalkyl; C₂₋₆ heterocyclyl; C₆₋₁₂aryl optionally substituted with 1 or more halo, hydroxyl, C₁₋₆ alkyland/or C₁₋₆ alkoxyl; and C₄₋₁₂ heteroaryl optionally substituted with 1or more halo, hydroxyl, C₁₋₆ alkyl and/or C₁₋₆ alkoxyl. R^(c) and R^(d)can both be hydrogen or each common substitutients such as: C₁₋₁₂ alkyl;C₂₋₁₂ alkenyl; C₃₋₁₂ cycloalkyl; C₂₋₆ heterocyclyl; C₆₋₁₂ aryloptionally substituted with 1 or more halo, hydroxyl, C₁₋₆ alkyl and/orC₁₋₆ alkoxyl; and C₄₋₁₂ heteroaryl optionally substituted with 1 or morehalo, hydroxyl, C₁₋₆ alkyl and/or C₁₋₆ alkoxyl. Alternatively, R^(c) andR^(d) together with the nitrogen they are attached to can form a ringstructure, such as a C₄₋₁₄ heteroaryl optionally substituted with 1 ormore halo, hydroxyl, C₁₋₆ alkyl and/or C₁₋₆ alkoxyl.

R^(3a) may be hydrogen, halo (e.g., bromo), hydroxyl, C₁₋₃ alkoxyl(e.g., methoxyl), cyano, carboxyl, or formamide. In certain embodiments,R^(3a) is hydrogen. In some embodiments, R^(3a) is bromo.

R^(4a) may be hydrogen, halo (e.g., bromo), hydroxyl, C₁₋₃ alkoxyl(e.g., methoxyl), cyano, carboxyl, or formamide. In certain embodiments,R^(4a) is hydrogen. In some embodiments, R^(4a) is bromo.

In certain embodiments, the presently disclosed embodiments include acompound or pharmaceutically acceptable salt thereof, for promotingneurogenesis and/or reducing neuronal cell death, the compound havingformula (III):

-   -   wherein R^(1b) is selected from the group consisting of:        hydrogen; C₁₋₆ alkyl optionally substituted with 1 or more halo,        hydroxyl, cyano and/or azide; —CH(R⁵)—C(O)—Z^(1b); and        —CH₂—C(R^(A1))(R^(A2))—CH₂—Z^(2b);        -   wherein R⁵ is hydrogen or C₁₋₃ alkyl;        -   wherein one of R^(A1) and R^(A2) is hydroxyl or halo and the            other is hydrogen;        -   wherein Z^(1b) is selected from the group consisting of:            hydroxyl; C₁₋₆ alkoxyl; and amine optionally substituted            with a hydroxyl, C₁₋₁₂ sulfonyl optionally substituted with            1-6 halo, C₆₋₁₂ aryl sulfonyl optionally substituted with            1-6 halo, C₄₋₁₂ heteroaryl sulfonyl optionally substituted            with 1-6 halo, C₂₋₁₂ carbonyl optionally substituted with            1-6 halo, and/or C₂₋₁₂ carboxyalkyl optionally substituted            with 1-6 halo;        -   wherein Z^(2b) is selected from the group consisting of:            C₁₋₃ alkyl, azide, and N(R⁶)(R⁷);        -   wherein R⁶ and R⁷ are each independently selected from the            group consisting of: hydrogen; carboxamide optionally            substituted with 1 or more C₁₋₆ alkyl, C₆₋₁₂ aryl and/or            C₄₋₁₂ heteroaryl; C₆₋₁₂ aryl optionally substituted with 1            or more halo, hydroxyl, C₁₋₆ alkyl and/or C₁₋₆ alkoxyl;            C₁₋₁₂ sulfonyl optionally substituted with 1-6 halo; C₆₋₁₂            aryl sulfonyl optionally substituted with 1-6 halo; and            C₄₋₁₂ heteroaryl sulfonyl optionally substituted with 1-6            halo; wherein no more than one of R⁶ and R⁷ is hydrogen; and    -   wherein R^(3b) and R^(4b) are each independently selected from        the group consisting of: hydrogen, halo, hydroxyl, C₁₋₃ alkoxyl,        cyano, carboxyl, and formamide.

In some embodiments, one or more of the following definitions apply:

-   -   (1) when R^(1b) is optionally substituted C₁₋₆ alkyl, R^(1b) is        selected from unsubstituted C₁₋₆ alkyl or C₃₋₆ alkyl substituted        with 1 hydroxyl or C₁₋₆ alkyl substituted with 1 cyano;    -   (2) when R^(1b) unsubstituted C₁₋₆ alkyl, R^(1b) is        unsubstituted C₂₋₆ alkyl;    -   (3) when R⁵ is hydrogen, Z^(1b) is amine optionally substituted        with a hydroxyl, C₁₋₁₂ sulfonyl optionally substituted with 1-6        halo, C₆₋₁₂ aryl sulfonyl optionally substituted with 1-6 halo,        C₄₋₁₂ heteroaryl sulfonyl optionally substituted with 1-6 halo,        C₂₋₁₂ carbonyl optionally substituted with 1-6 halo, and/or        C₂₋₁₂ carboxyalkyl optionally substituted with 1-6 halo; and/or    -   (4) Z^(2b) is azide or N(R⁶)(R⁷).

For example, R^(1b) may be hydrogen. R^(1b) may also be C₁₋₆ alkyloptionally substituted with 1 or more halo, hydroxyl, cyano and/orazide, such as unsubstituted C₁₋₆ alkyl (e.g., methyl, ethyl, n-propyl,isopropyl, or tert-butyl) or C₃₋₆ alkyl substituted with 1 hydroxyl(e.g., at the beta-carbon) or C₁₋₆ alkyl substituted with 1 cyano.R^(1b) may also be —CH(R⁵)—C(O)—Z^(1b) or—CH₂—C(R^(A1))(R^(A2))—CH₂—Z^(2b).

R⁵ can be hydrogen or C₁₋₃ alkyl (e.g., methyl). Z^(1b) can be hydroxylor C₁₋₆ alkoxyl. Z^(1b) can also be amine optionally substituted with 1hydroxyl, or amine optionally substituted with C₁₋₁₂ sulfonyl, C₆₋₁₂aryl sulfonyl, C₄₋₁₂ heteroaryl sulfonyl, C₂₋₁₂-carbonyl, or C₂₋₁₂carboxyalkyl (e.g., —CH₂C(O)OH). The C₁₋₁₂ sulfonyl, C₆₋₁₂ arylsulfonyl, C₄₋₁₂ heteroaryl sulfonyl, C₂₋₁₂ carbonyl, and C₂₋₁₂carboxyalkyl groups can contain one or more common substitutients suchas alkyl, halo, hydroxyl, alkoxyl, aryl and/or heteroaryl.

One of R^(A1) and R^(A2) can be hydroxyl or halo (e.g., fluoro) and theother of R^(A1) and R^(A2) can be hydrogen. Alternatively, both R^(A1)and R^(A2) can be hydrogen. Z^(2b) can be C₁₋₃ alkyl. Z^(2b) can also beazide or N(R⁶)(R⁷). R⁶ and R⁷ can both be hydrogen. Alternatively, onlyone of R⁶ and R⁷ is hydrogen, or none of R⁶ and R⁷ is hydrogen. R⁶ andR⁷ can also be carboxamide optionally substituted with 1 or more C₁₋₆alkyl, C₆₋₁₂ aryl and/or C₄₋₁₂ heteroaryl; C₆₋₁₂ aryl optionallysubstituted with 1 or more halo, hydroxyl, C₁₋₆ alkyl and/or C₁₋₆alkoxyl; C₁₋₁₂ sulfonyl optionally substituted with 1-6 halo; C₆₋₁₂ arylsulfonyl optionally substituted with 1-6 halo; or C₄₋₁₂ heteroarylsulfonyl optionally substituted with 1-6 halo.

R^(3b) may be hydrogen, halo (e.g., bromo), hydroxyl, C₁₋₃ alkoxyl(e.g., methoxyl), cyano, carboxyl, or formamide. In certain embodiments,R^(3b) is hydrogen. In some embodiments, R^(3b) is bromo.

R^(4b) may be hydrogen, halo (e.g., bromo), hydroxyl, C₁₋₃ alkoxyl(e.g., methoxyl), cyano, carboxyl, or formamide. In certain embodiments,R^(4b) is hydrogen. In some embodiments, R^(4b) is bromo.

For example, both R^(3b) and R^(4b) are hydrogen. Both R^(3b) and R^(4b)can be bromo.

In certain embodiments, the presently disclosed embodiments include acompound or pharmaceutically acceptable salt thereof, for promotingneurogenesis and/or reducing neuronal cell death, the compound havingformula (IV):

-   -   wherein:    -   R^(1c) is selected from the group consisting of: hydrogen, C₁₋₆        alkyl, C₁₋₆ carboxyalkyl, C₁₋₁₂ sulfonyl optionally substituted        with 1-6 halo, C₆₋₁₂ aryl sulfonyl optionally substituted with        1-6 halo and C₄₋₁₂ heteroaryl sulfonyl optionally substituted        with 1-6 halo;    -   R^(2c) is selected from the group consisting of: hydrogen;        hydroxyl; cyano; halo; amine optionally substituted with 1 or        more C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, aryl, and/or        heteroaryl; and C₁₋₁₂ alkoxyl;    -   R^(3c) is selected from the group consisting of: carboxyl; C₁₋₆        alkoxycarbonyl; hydroxyl; C₁₋₁₂ alkoxyl; cyano; halo; and amine        optionally substituted with 1 or more C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₃₋₆ cycloalkyl, aryl, and/or heteroaryl;    -   R^(4c) is selected from the group consisting of: hydrogen, halo,        hydroxyl, and C₁₋₃ alkoxyl; and one or both of Q₁ and Q₂ are        nitrogen.

In some embodiments, one or more of the following definitions apply:

-   -   (1) R^(2c) is hydrogen; hydroxyl; or C₁₋₁₂ alkoxyl; and/or    -   (2) R^(3c) is carboxyl; C₁₋₆ alkoxycarbonyl; hydroxyl; or amine        substituted with 1-2 C₁₋₆ alkyl.

For example, R^(1c) can be hydrogen. R^(1c) can also be C₁₋₆ alkyl orC₂₋₆-carboxyalkyl (e.g., —CH₂C(O)OH). R^(1c) can also be C₁₋₁₂ sulfonyloptionally substituted with 1-6 halo or C₆₋₁₂ aryl sulfonyl (e.g.,—S(O)₂Ph) optionally substituted with 1-6 alkyl, substituted alkyl(e.g., CF₃) and/or halo. R^(1c) can also be C₄₋₁₂ heteroaryl sulfonyloptionally substituted with 1-6 alkyl, substituted alkyl (e.g., CF₃)and/or halo.

R^(2c) can be hydrogen or hydroxyl. R^(2c) can also be cyano; halo; oramine optionally substituted with 1 or more C₁₋₆ alkyl, C₂₋₆ alkenyl,C₃₋₆ cycloalkyl, aryl, and/or heteroaryl. R^(2c) can also be C₁₋₁₂alkoxyl.

R^(3c) can be carboxyl or C₁₋₆ alkoxycarbonyl (e.g., —C(O)OCH₃ or—C(O)OCH₂CH₃). R^(3c) can also be hydroxyl. R^(3c) can also be C₁₋₁₂alkoxyl; cyano; or halo (e.g., bromo). R^(3c) can also be amineoptionally substituted with 1 or more C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, aryl, and/or heteroaryl, such as N(CH₃)₂.

R^(4c) can be hydrogen or halo (e.g., bromo). R^(4c) can also behydroxyl or and C₁₋₃ alkoxyl.

Q₁ and Q₂ can both be nitrogen. Alternatively, one of Q₁ and Q₂ isnitrogen and the other of Q₁ and Q₂ is carbon. In some embodiments, whenboth Q₁ and Q₂ are be nitrogen and both R^(2c) and R^(3c) are hydroxyl,the corresponding ring structure is typically represented by:

In certain embodiments, the presently disclosed embodiments include acompound or pharmaceutically acceptable salt thereof, for promotingneurogenesis and/or reducing neuronal cell death, the compound havingformula (V):

-   -   wherein R^(1d) is selected from the group consisting of:        hydrogen and CH₂—C(R^(A1))(R^(A2))—CH₂—N(R⁶)(R⁷);        -   wherein one of R^(A1) and R^(A2) is hydroxyl or halo and the            other is hydrogen; and        -   wherein R⁶ and R⁷ are each independently selected from the            group consisting of:

hydrogen; C₆₋₁₂ aryl optionally substituted with 1 or more halo,hydroxyl, C₁₋₆ alkyl and/or C₁₋₆ alkoxyl; and C₄₋₁₂ heteroaryloptionally substituted with 1 or more halo, hydroxyl, C₁₋₆ alkyl and/orC₁₋₆ alkoxyl;

-   -   wherein R^(2d) is selected from the group consisting of: halo,        hydroxyl, C₁₋₁₂ alkoxyl, cyano, aryl, and heteroaryl;    -   wherein R^(3d) is selected from the group consisting of:        hydrogen and amine optionally substituted with 1 or more C₁₋₆        alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₂₋₆ heterocyclyl, aryl,        and/or heteroaryl; and    -   wherein R^(4d) is selected from the group consisting of:        hydrogen, halo, hydroxyl, and C₁₋₃ alkoxyl.

In some embodiments, R^(2d) is cyano, and/or R^(4d) is hydrogen, bromoor methoxy.

For example, R^(1d) can be hydrogen. R^(1d) can also beCH₂—C(R^(A1))(R^(A2))—CH₂—N(R⁶)(R⁷). One of R^(A1) and R^(A2) can behydroxyl and the other is hydrogen. One of R^(A1) and R^(A2) can be halo(e.g., fluoro) and the other is hydrogen. Alternatively, both R^(A1) andR^(A2) can be hydrogen. R⁶ and R⁷ can both be hydrogen. Alternatively,one or both of R⁶ and R⁷ can be C₆₋₁₂ aryl optionally substituted with 1or more halo, hydroxyl, C₁₋₆ alkyl and/or C₁₋₆ alkoxyl; or C₄₋₁₂heteroaryl optionally substituted with 1 or more halo, hydroxyl, C₁₋₆alkyl and/or C₁₋₆ alkoxyl.

R^(2d) can be halo, hydroxyl, or C₁₋₁₂ alkoxyl. R^(2d) can also becyano. R^(2d) can also be aryl (e.g., C₆₋₁₂) or heteroaryl (e.g.,C₄₋₁₂).

R^(3d) can be hydrogen. R^(3d) can also be amine optionally substitutedwith 1 or more C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₂₋₆heterocyclyl, aryl (e.g., C₆₋₁₂), and/or heteroaryl (e.g., C₄₋₁₂).

R^(4d) can be hydrogen, halo (e.g., bromo), hydroxyl, or C₁₋₃ alkoxyl(e.g., methoxyl).

Compounds or salts thereof having any combinations of the abovedefinitions of the various groups are all included in the presentlydisclosed embodiments.

The presently disclosed embodiments also include compositions (e.g.,pharmaceutical compositions) that include such compounds as well asmethods of making, identifying, and using such compounds. Other featuresand advantages are described in, or will be apparent from, the presentspecification and accompanying drawings.

Any of the compounds disclosed herein can be used in any of the methodsor compositions described anywhere herein. The presently disclosedembodiments relate generally to stimulating neurogenesis (e.g.,post-natal neurogenesis, e.g., post-natal hippocampal and/orhypothalamic neurogenesis) and protecting neurons from death with acompound of any of the formulae described herein or a salt (e.g., apharmaceutically acceptable salt) thereof as defined anywhere herein.

For example, methods of promoting the generation of neurons arefeatured. As another example, methods of promoting the survival, growth,development and/or function of neurons, particularly CNS, brain,cerebral, hippocampal and hypothalamic neurons are featured. As afurther example, methods of stimulating post-natal hippocampal and/orhypothalamic neurogenesis are featured.

In some embodiments, such methods can include in vitro methods, e.g.,contacting a sample (e.g., a cell or tissue) with a compound of any ofthe formulae described herein or a salt (e.g., a pharmaceuticallyacceptable salt) thereof as defined anywhere herein. In otherembodiments, the methods can include administering a compound of any ofthe formulae described herein or a salt (e.g., a pharmaceuticallyacceptable salt) thereof as defined anywhere herein to a subject (e.g.,a mammal, such as a human).

Accordingly, in an aspect, the presently disclosed embodiments includeand feature methods of screening for (thereby identifying) compoundsthat stimulate neurogenesis (e.g., post-natal neurogenesis, e.g.,post-natal hippocampal and/or hypothalamic neurogenesis) or protectnewborn neurons from cell death.

In another aspect, methods for treating (e.g., controlling, relieving,ameliorating, alleviating, or slowing the progression of) or methods forpreventing (e.g., delaying the onset of or reducing the risk ofdeveloping) one or more diseases, disorders, or conditions caused by, orassociated with insufficient (e.g., aberrant) neurogenesis or unwantedneuronal cell death in a subject in need thereof are featured. Themethods include administering to the subject an effective amount of acompound of any of the formulae described herein or a salt (e.g., apharmaceutically acceptable salt) thereof as defined anywhere herein tothe subject.

In another aspect, the use of a compound of any of the formulaedescribed herein or a salt (e.g., a pharmaceutically acceptable salt)thereof as defined anywhere herein in the preparation of, or for use as,a medicament for the treatment (e.g., controlling, relieving,ameliorating, alleviating, or slowing the progression of) or prevention(e.g., delaying the onset of or reducing the risk of developing) of oneor more diseases, disorders, or conditions caused by, or associatedwith, insufficient (e.g., aberrant) neurogenesis or unwanted neuronalcell death is featured.

In some embodiments, the one or more diseases, disorders, or conditionscan include neuropathies, nerve trauma, and neurodegenerative diseases.In some embodiments, the one or more diseases, disorders, or conditionscan be diseases, disorders, or conditions caused by, or associated withinsufficient neurogenesis (e.g., aberrant hippocampal and/orhypothalamic neurogenesis) as is believed to occur in neuropsychiatricdiseases, or aberrant neuronal cell death as is believed to occur inneurodegenerative diseases. Examples of the one or more diseases,disorders, or conditions include, but are not limited to, schizophrenia,major depression, bipolar disorder, normal aging, epilepsy, traumaticbrain injury, post-traumatic stress disorder, Parkinson's disease,Alzheimer's disease, Down syndrome, spinocerebellar ataxia, amyotrophiclateral sclerosis, Huntington's disease, stroke, radiation therapy,chronic stress, and abuse of neuro-active drugs (such as alcohol,opiates, methamphetamine, phencyclidine, and cocaine), retinaldegeneration, spinal cord injury, peripheral nerve injury, physiologicalweight loss associated with various conditions, and cognitive declineassociated with normal aging, radiation therapy, and chemotherapy.

In some embodiments, the subject can be a subject in need thereof (e.g.,a subject identified as being in need of such treatment, such as asubject having, or at risk of having, one or more of the diseases orconditions described herein). Identifying a subject in need of suchtreatment can be in the judgment of a subject or a health careprofessional and can be subjective (e.g. opinion) or objective (e.g.measurable by a test or diagnostic method). In some embodiments, thesubject can be a mammal. In certain embodiments, the subject can be ahuman.

In some embodiments, methods of making the compounds described hereinare featured. In embodiments, the methods include taking any one of theintermediate compounds described herein and reacting it with one or morechemical reagents in one or more steps to produce a compound of any ofthe formulae described herein or a salt (e.g., a pharmaceuticallyacceptable salt) thereof as defined anywhere herein.

In some embodiments, methods of making the pharmaceutical compositionsdescribed herein are featured. In embodiments, the methods includetaking any one or more of the compounds of any of the other formulaedescribed herein or a salt (e.g., a pharmaceutically acceptable salt)thereof as defined anywhere herein, and mixing said compound(s) with oneor more pharmaceutically acceptable carriers. In one aspect, kits forthe treatment (e.g., controlling, relieving, ameliorating, alleviating,or slowing the progression of) or prevention (e.g., delaying the onsetof or reducing the risk of developing) of one or more diseases,disorders, or conditions caused by, or associated with insufficient(e.g., aberrant) neurogenesis or unwanted neuronal cell death arefeatured. The kits include (i) a compound of any of the formulaedescribed herein or a salt (e.g., a pharmaceutically acceptable salt)thereof as defined anywhere herein; and (ii) instructions that include adirection to administer said compound to a subject (e.g., a patient).

In various embodiments, compounds of formula (I), (II), (III), (IV) and(V) can be used in a method for the treatment of a disease, disorder, orcondition caused by unwanted neuronal cell death or associated withinsufficient neurogenesis in a subject in need thereof. The method caninclude administering to the subject an effective amount of a compoundhaving formula (I), (II), (III), (VI), or (V) or a pharmaceuticallyacceptable salt thereof, as defined herein.

The methods can further include detecting a resultant neurotrophism(e.g., neurogenesis; and/or determining that the patient has aberrantneurotrophism, particularly aberrant neurogenesis, particularly aberranthippocampal and/or hypothalamic neurogenesis, or a disease or disorderassociated therewith, particularly by detecting and/or diagnosing thesame.

The methods can further include detecting determining that the subjecthas aberrant neurogenesis or death of neurons or a disease or disorderassociated therewith, by detecting the same in said subject.

The methods can further include detecting a resultant hippocampal and/orhypothalamic neurogenesis. The compounds of the presently disclosedembodiments may be used to block neuron cell death in a manner that notonly protects mature neurons, but also augments hippocampal neurogenesisby promoting survival of newborn neurons. In some embodiments, thecompounds of the presently disclosed embodiments may have apro-neurogenic activity that is attributable to their ability to impedethe death of newborn hippocampal neurons. Instead of stimulating thebirth of neuronal stem cells, the compounds may favor their post-birthsurvival along the differentiation pathway required for them to evolveinto properly wired, granular neurons. In the absence of compoundadministration, upwards of 80% of newborn neurons die. Administration ofthe compounds of the presently disclosed embodiments can significantlyenhance the survival of newborn hippocampal neurons in the adult brain.

The disease, disorder, or condition can be a neuropsychiatric andneurodegenerative disease, including (but not limited to) schizophrenia,major depression, bipolar disorder, normal aging, epilepsy, traumaticbrain injury, post-traumatic stress disorder, Parkinson's disease,Alzheimer's disease, Down syndrome, spinocerebellar ataxia, amyotrophiclateral sclerosis, Huntington's disease, stroke, radiation therapy,chronic stress, and abuse of neuro-active drugs (such as alcohol,opiates, methamphetamine, phencyclidine, and cocaine), retinaldegeneration, spinal cord injury, peripheral nerve injury, physiologicalweight loss associated with various conditions, and cognitive declineassociated with normal aging, and chemotherapy.

In certain embodiments, the compounds of the presently disclosedembodiments can be used to treat a depressive disorder. For example, thecompounds may augment ghrelin-induced hippocampal neurogenesis, therebytreating the depressice disorder. The depressive disorder can beassociated with insufficient ghrelin response. In an embodiment, theinsufficient ghrelin response may result in impaired or reducedhippocampal neurogenesis.

In some embodiments, the compounds or salt (e.g., a pharmaceuticallyacceptable salt) thereof provide at least about 27 (×10⁻⁰⁶) BrdU+cells/mm³ dentate gyms when evaluated in the assay described inconjunction with Table 1 (i.e., evaluated for pro-neurogenicefficacy/neuroprotection in a standard in vivo hippocampal neurogenesisassay at 10 μM concentration in four 12 week old adult male C57/B16mice.

In some embodiments, the compounds or salt (e.g., a pharmaceuticallyacceptable salt) thereof provide at least about 19 (×10⁻⁰⁶) BrdU+cells/mm³ dentate gyms when evaluated in the hippocampal neurogenesisassay described in conjunction with Table 1.

In some embodiments, the compounds or salt (e.g., a pharmaceuticallyacceptable salt) thereof provide from about 18 to about 30 (e.g., 18-27,19-26, 20-25, 27-30, 27-29) (×10⁻⁰⁶) BrdU+ cells/mm³ dentate gyms whenevaluated in the hippocampal neurogenesis assay described in conjunctionwith Table 1.

In some embodiments, the compounds or salt (e.g., a pharmaceuticallyacceptable salt) thereof provide from about 18 to about 26 (e.g., 19-26,20-25) (×10⁻⁰⁶) BrdU+ cells/mm³ dentate gyms when evaluated in thehippocampal neurogenesis assay described in conjunction with Table 1.

In some embodiments, the compounds or salt (e.g., a pharmaceuticallyacceptable salt) thereof provide from about 27 to about 30 (e.g., 27-29)(×10⁻⁰⁶) BrdU+ cells/mm³ dentate gyms when evaluated in the hippocampalneurogenesis assay described in conjunction with Table 1.

In embodiments, a composition (e.g., a pharmaceutical composition) caninclude an amount effective to achieve the levels described above.

In embodiments, any compound, composition, or method described hereincan also include any one or more of the other features delineated in thedetailed description and/or in the claims.

DETAILED DESCRIPTION

Provided herein are embodiments related generally to stimulatingneurogenesis (e.g., post-natal neurogenesis, e.g., post-natalhippocampal and/or hypothalamic neurogenesis) and/or promoting thesurvival of existing neurons by reducing neuronal cell death.

In certain embodiments, the compounds described herein may beneurotrophic. By “neurotrophic” it is generally meant that the compoundsmay exert survival-promoting and/or trophic actions on existing neuronalcells, and/or stimulate generation of new neurons.

In certain embodiments, the compounds described herein may bepro-neurogenic and/or neuroprotective. By “pro-neurogenic” it isgenerally meant that the compounds may be useful in promoting,stimulating and/or enhancing neurogenesis, which is the generation ofnew neurons. By “neuroprotective” it is generally meant that thecompounds may protect or prevent neuronal cells from cell death orapoptosis.

The neurotrophic, pro-neurogenic and/or neuroprotective compoundsdescribed herein are attractive candidates as therapeutic agents in manyclinical conditions and neuropsychiatric or neurodegenerative diseasessuch as schizophrenia, major depression, bipolar disorder, normal aging,epilepsy, traumatic brain injury, post-traumatic stress disorder,Parkinson's disease, Alzheimer's disease, Down syndrome, spinocerebellarataxia, amyotrophic lateral sclerosis, Huntington's disease, stroke,radiation therapy, chronic stress, abuse of a neuro-active drug, retinaldegeneration, spinal cord injury, peripheral nerve injury, physiologicalweight loss associated with various conditions, as well as cognitivedecline associated with normal aging, chemotherapy, and the like.

DEFINITIONS

“An effective amount” refers to an amount of a compound that confers atherapeutic effect (e.g., treats, e.g., controls, relieves, ameliorates,alleviates, or slows the progression of; or prevents, e.g., delays theonset of or reduces the risk of developing, a disease, disorder, orcondition or symptoms thereof; on the treated subject. The therapeuticeffect may be objective (i.e., measurable by some test or marker) orsubjective (i.e., subject gives an indication of or feels an effect). Aneffective amount of the compound described above may range from about0.01 mg/kg to about 1000 mg/kg, (e.g., from about 0.1 mg/kg to about 100mg/kg, from about 1 mg/kg to about 100 mg/kg). Effective doses will alsovary depending on route of administration, as well as the possibility ofco-usage with other agents.

The term “halo” or “halogen” refers to any radical of fluorine,chlorine, bromine or iodine.

In general, and unless otherwise indicated, substituent (radical) prefixnames are derived from the parent hydride by either (i) replacing the“ane” in the parent hydride with the suffixes “yl,” “diyl,” “triyl,”“tetrayl,” etc.; or (ii) replacing the “e” in the parent hydride withthe suffixes “yl,” “diyl,” “triyl,” “tetrayl,” etc. (here the atom(s)with the free valence, when specified, is (are) given numbers as low asis consistent with any established numbering of the parent hydride).Accepted contracted names, e.g., adamantyl, naphthyl, anthryl,phenanthryl, furyl, pyridyl, isoquinolyl, quinolyl, and piperidyl, andtrivial names, e.g., vinyl, phenyl, and thienyl are also used hereinthroughout. Conventional numbering/lettering systems are also adhered tofor substituent numbering and the nomenclature of fused, bicyclic,tricyclic, polycyclic rings.

The following definitions are used, unless otherwise described. Specificand general values listed below for radicals, substituents, and ranges,are for illustration only; they do not exclude other defined values orother values within defined ranges for the radicals and substituents.Unless otherwise indicated, alkyl, alkoxy, alkenyl, and the like denoteboth straight and branched groups.

The term “alkyl” refers to a saturated hydrocarbon chain that may be astraight chain or branched chain, containing the indicated number ofcarbon atoms. For example, C₁₋₆ alkyl indicates that the group may have1 to 6 (inclusive) carbon atoms in it. Any atom can be optionallysubstituted, e.g., by one or more substituents. Examples of alkyl groupsinclude without limitation methyl, ethyl, n-propyl, isopropyl, andtert-butyl.

As referred to herein, the term “alkoxy” refers to a group of formula—O(alkyl). Alkoxy can be, for example, methoxy (—OCH₃), ethoxy, propoxy,isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 2-pentoxy,3-pentoxy, or hexyloxy. As used herein, the term “hydroxyl,” employedalone or in combination with other terms, refers to a group of formula—OH.

The term “alkenyl” refers to a straight or branched hydrocarbon chaincontaining the indicated number of carbon atoms and having one or morecarbon-carbon double bonds. Any atom can be optionally substituted,e.g., by one or more substituents. Alkenyl groups can include, e.g.,vinyl, allyl, 1-butenyl, and 2-hexenyl. One of the double bond carbonscan optionally be the point of attachment of the alkenyl substituent.

The term “alkynyl” refers to a straight or branched hydrocarbon chaincontaining the indicated number of carbon atoms and having one or morecarbon-carbon triple bonds. Alkynyl groups can be optionallysubstituted, e.g., by one or more substituents. Alkynyl groups caninclude, e.g., ethynyl, propargyl, and 3-hexynyl. One of the triple bondcarbons can optionally be the point of attachment of the alkynylsubstituent.

The term “heterocyclyl” refers to a fully saturated monocyclic,bicyclic, tricyclic or other polycyclic ring system having one or moreconstituent heteroatom ring atoms independently selected from O, N (itis understood that one or two additional groups may be present tocomplete the nitrogen valence and/or form a salt), or S. The heteroatomor ring carbon can be the point of attachment of the heterocyclylsubstituent to another moiety. Any atom can be optionally substituted,e.g., by one or more substituent. Heterocyclyl groups can include, e.g.,tetrahydrofuryl, tetrahydropyranyl, piperidyl (piperidine), piperazinyl,morpholinyl (morpholino), pyrrolinyl, and pyrrolidinyl. By way ofexample, the phrase “heterocyclic ring containing from 5-6 ring atoms,wherein 1-2 of the ring atoms is independently selected from N, NH,N(C₁-C₆ alkyl), NC(O)(C₁-C₆ alkyl), O, and S; and wherein saidheterocyclic ring is optionally substituted with 1-3 independentlyselected R^(a)″ would include (but not be limited to) tetrahydrofuryl,tetrahydropyranyl, piperidyl (piperidino), piperazinyl, morpholinyl(morpholino), pyrrolinyl, and pyrrolidinyl.

The term “cycloalkyl” refers to a fully saturated monocyclic, bicyclic,tricyclic, or other polycyclic hydrocarbon groups. Any atom can beoptionally substituted, e.g., by one or more substituents. A ring carbonserves as the point of attachment of a cycloalkyl group to anothermoiety. Cycloalkyl moieties can include, e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and norbornyl(bicycle[2.2.1]heptyl).

The term “aryl” refers to an aromatic monocyclic, bicyclic (2 fusedrings), or tricyclic (3 fused rings), or polycyclic (>3 fused rings)hydrocarbon ring system. One or more ring atoms can be optionallysubstituted, e.g., by one or more substituents. Aryl moieties include,e.g., phenyl and naphthyl.

The term “heteroaryl” refers to an aromatic monocyclic, bicyclic (2fused rings), tricyclic (3 fused rings), polycyclic (>3 fused rings)hydrocarbon groups having one or more heteroatom ring atomsindependently selected from O, N (it is understood that one or twoadditional groups may be present to complete the nitrogen valence and/orform a salt), or S. One or more ring atoms can be optionallysubstituted, e.g., by one or more substituents. Examples of heteroarylgroups include, but are not limited to, 2H-pyrrolyl, 3H-indolyl,acridinyl, benzo[b]thienyl, benzothiazolyl, P-carbolinyl, carbazolyl,coumarinyl, chromenyl, dibenzo[b,d]furanyl, furazanyl, furyl,imidazolyl, imidizolyl, indazolyl, isobenzofuranyl, isoquinolyl,isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, perimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,pyrimidinyl, pyrrolyl quinazolinyl quinolyl quinoxalinyl, thiadiazolyl,thianthrenyl, thiazolyl, thienyl, triazolyl, and xanthenyl.

The descriptors “C═O” or “C(O)” refers to a carbon atom that is doublybonded to an oxygen atom. Similarly, “S(O)” refers to a sulfur atom thatis doubly bonded to an oxygen atom.

The term “carboxyl” refers to a group of formula C(O)OH. The term“alkoxycarbonyl” refers to a group of formula. The term “carboxyalkyl”refers to a group of formula (alkyl)-C(O)OH wherein the carboxyl groupmay be attached to any carbon atom in the alkyl group.

As used herein, the term “cyano,” employed alone or in combination withother terms, refers to a group of formula —CN, wherein the carbon andnitrogen atoms are bound together by a triple bond. In general, when adefinition for a particular variable includes both hydrogen andnon-hydrogen (halo, alkyl, aryl, etc.) possibilities, the term“substituent(s) other than hydrogen” refers collectively to thenon-hydrogen possibilities for that particular variable.

The term “substituent” refers to a group “substituted” on, e.g., analkyl, haloalkyl, cycloalkyl, heterocyclyl, heterocycloalkenyl,cycloalkenyl, aryl, or heteroaryl group at any atom of that group. Inone aspect, the substituent(s) on a group are independently any onesingle, or any combination of two or more of the permissible atoms orgroups of atoms delineated for that substituent. In another aspect, asubstituent may itself be substituted with any one of the abovesubstituents. Further, as used herein, the phrase “optionallysubstituted” means unsubstituted (e.g., substituted with an H) orsubstituted. As used herein, the term “substituted” means that ahydrogen atom is removed and replaced by a substituent. It is understoodthat substitution at a given atom is limited by valency.

Compounds

Compounds of formula (I)-(V) as defined herein, or any combinations ofthe definitions of the various groups, are encompassed by the presentlydisclosed embodiments. Various compounds will be further described inthe following examples. It should be understood that these examples arefor illustrative purposes only and are not to be construed as limitingthe presently disclosed embodiments in any manner.

P7C3-S132:1-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-3-(1H-indol-1-yl)propan-2-olStep 1: Synthesis of5-(oxiran-2-ylmethyl)-10,11-dihydro-5H-dibenzo[b,f]azepine

n-BuLi (25.6 mL, 40.9 mmol) was added to a stirred solution ofiminodibenzyl (4.00 g, 20.2 mmol) in dry THF (24 mL) at −78° C. andunder atmosphere of N₂. The mixture was allowed to stir at the sametemperature for 20 min and then epibromohydrin (8.48 mL, 102 mmol) wasadded. The resulting mixture was stirred overnight allowing the reactionto warm up to room temperature. Upon completion, the reaction waspartitioned between EtOAc and H₂O. The aqueous layer was washed withEtOAc. The combined organic extracts were washed with brine, dried overMgSO₄, filtered, and concentrated in vacuo. The crude residue waspurified by chromatography (SiO₂, 98:2 Hexanes/EtOAc) to afford thedesired product as colorless solid (3.00 g, 59%). The spectroscopic datawere in full agreement with those reported in the literature (Levy, O.;Erez, M.; Varon, D.; Keinan, E. Bioorg. Med. Chem. Lett. 2001, 11,2921-2926).

Step 2:1-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-3-(1H-indol-1-yl)propan-2-ol.(P7C3-S132)

Indole (36.0 mg, 0.30 mmol) was added to a suspension of NaH (20.0 mg,0.48 mmol) in of DMF (5 mL) at 0° C. The mixture was allowed to stir at0° C. for 10 min and then at room temperature for 30 min.5-(oxiran-2-ylmethyl)-10,11-dihydro-5H-dibenzo[b,f]azepine (75.0 mg,0.30 mmol) was then added and the reaction mixture was stirred overnightat room temperature. Upon completion, the reaction was partitionedbetween EtOAc and H₂O. The aqueous layer was washed EtOAc. The combinedorganic extracts were washed with brine, dried over MgSO₄, filtered, andconcentrated in vacuum. The crude residue was purified by chromatography(SiO₂, 9:1 Hexanes/EtOAc) to afford the desired product as colorlesssolid (90.3 mg, 82%).

¹H NMR (CDCl₃, 500 MHz) δ 7.60 (d, 1H, J=7.2 Hz), 7.18-7.05 (m, 7H),7.05-6.95 (m, 5H), 6.47 (d, 1H, J=2.8 Hz), 4.36 (dd, 1H, J=3.2, 14.4Hz), 4.20 (m_(c), 1H), 4.05 (dd, 1H, J=7.5, 14.5 Hz), 3.80 (d, 2H, J=6.5Hz), 3.27-3.18 (m, 4H), 2.14 (br s, 1H). ¹³C NMR (CDCl₃, 126 MHz) δ147.9, 136.4, 134.3, 130.4, 128.9, 128.8, 127.0, 123.6, 121.8, 121.2,119.9, 119.7, 109.5, 101.8, 68.3, 54.4, 50.6, 32.3. MS (ESI) m/z: 369.0[M+H]⁺ ([M+H]⁺ for C₂₅H₂₅N₂O requires 369.1).

P7C3-S133:1-(9H-carbazol-9-yl)-3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)propan-2-ol

Following the same procedure as for P7C3-S132, P7C3-S133 was preparedfrom 5-(oxiran-2-ylmethyl)-10,11-dihydro-5H-dibenzo[b,f]azepine (75.0mg, 0.30 mmol) and 9H-carbazole (51 mg, 0.3 mmol) with NaH (20.0 mg,0.48 mmol) in DMF (5 mL) and isolated as a colorless solid (101.4 mg,81%).

¹H NMR (CDCl₃, 500 MHz) δ 8.10 (d, 2H, J=7.7 Hz), 7.40 (m_(c), 2H),7.29-7.13 (m, 8H), 7.10-7.01 (m, 4H), 4.51 (dd, 1H, J=2.7, 14.7 Hz),4.43 (m_(c), 1H), 4.35 (dd, 1H, J=7.9, 14.6 Hz), 4.01 (dd, 1H, J=6.5,12.7 MHz), 3.90 (dd, 1H, J=6.6, 12.7 MHz), 3.33-3.23 (m, 4H), 2.14 (brs, 1H). ¹³C NMR (CDCl₃, 126 MHz) δ 147.9, 141.0, 134.3, 130.4, 127.0,126.0, 123.6, 123.1, 120.4, 119.9, 119.4, 109.1, 68.2, 54.6, 47.7, 32.3.MS (ESI) m/z: 419.0 [M+H]⁺ ([M+H]⁺ for C₂₉H₂₇N₂O requires 419.2).

P7C3-S134:1-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-3-(phenylthio)propan-2-ol

Benzenethiol (34 μL, 0.33 mmol) was added to a solution of5-(oxiran-2-ylmethyl)-10,11-dihydro-5H-dibenzo[b,f]azepine (75.0 mg,0.30 mmol) in MeOH (5.6 mL) at room temperature. The reaction mixturewas heated to 80° C. and stirred overnight at the same temperature. Thereaction was monitored by LC/MS for the consumption of startingmaterial. The reaction was cooled to room temperature, diluted withEtOAc and washed with H₂O and brine. The organic layer was dried overNa₂SO₄, filtered and condensed. The crude residue was purified bychromatography (SiO₂, 9:1 Hexanes/EtOAc) to afford the desired product(66.0 mg, 61%).

¹H NMR (CDCl₃, 500 MHz) δ 7.19-7.05 (m, 11H), 6.96 (m_(c), 2H), 3.97(m_(c), 1H), 3.89 (d, 1H, J=6.3 Hz), 3.26 (dd, 2H, J=4.1, 13.9 Hz), 3.18(s, 4H), 2.96 (dd, 1H, J=7.3, 13.9 Hz). ¹³C NMR (CDCl₃, 126 MHz) δ147.9, 134.2, 130.2, 129.1, 126.8, 126.2, 123.3, 119.9, 66.9, 55.7,39.2, 32.3. MS (ESI) m/z: 361.9 [M+H]⁺ ([M+H]⁺ for C₂₃H₂₄NOS requires362.1).

P7C3-S135:1-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-3-phenoxypropan-2-ol

To a stirred solution of iminodibenzyl (75 mg, 0.38 mmol) in dry THF(1.5 mL) was added n-BuLi (0.3 mL, 0.68 mmol, 2.5 M in hexanes) at −78°C. and the resulting mixture was stirred for 30 min.2-(phenoxymethyl)oxirane (0.13 mL, 0.95 mL) was added and the reactionwas allowed to warm slowly to ambient temperature and stirred overnight.Upon completion, the reaction was quenched with saturated aqueous NH₄Cland the mixture was extracted with EtOAc. The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered, and concentrated.The crude residue was purified by chromatography (SiO₂, 9:1Hexanes/EtOAc) to afford the desired product (92.0 mg, 70%).

¹H NMR (CDCl₃, 500 MHz) δ 7.29 (t, 2H, J=8.0 Hz), 7.20-7.11 (m, 6H),7.02-6.95 (m, 3H), 6.88 (d, 2H, J=8.5 Hz), 4.23 (m_(c), 1H), 4.11 (dd,2H, J=3.7, 9.6 Hz), 4.06-3.95 (m, 2H), 3.21 (s, 4H). ¹³C NMR (CDCl₃, 126MHz) δ 158.6, 148.0, 134.4, 130.2, 129.6, 126.8, 123.3, 121.2, 119.9,114.6, 70.3, 67.4, 53.7, 32.2. MS (ESI) m/z: 346.0 [M+H]⁺ ([M+H]⁺ forC₂₃H₂₄NO₂ requires 346.1).

P7C3-S139:1-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-3-(dimethylamino)propan-2-ol

5-(Oxiran-2-ylmethyl)-10,11-dihydro-5H-dibenzo[b,f]azepine (75 mg, 0.3mmol) was added to a 25 mL scintillation vial followed by Me₂NH.HCl(37.0 mg, 0.45 mmol) and K₂CO₃ (125 mg, 0.9 mmol). The vial was heatedto reflux for 2 h. Upon completion the reaction was cooled to roomtemperature, the solids were filtered off and the solvent was evaporatedin vacuum. The crude residue was purified by chromatography (SiO₂, 98:2CH₂Cl₂/MeOH+1% NH₄OH) to afford the desired product as a white solid(76.0 mg, 86%).

¹H NMR (CDCl₃, 500 MHz) δ 7.10-7.00 (m, 6H), 6.87 (m_(c), 2H), 3.86-3.75(m, 2H), 3.73 (brs, 1H), 3.58 (dd, 1H, J=6.2, 12.2 Hz), 3.11 (s, 4H),2.41-2.28 (m, 2H), 2.09 (s, 6H). ¹³C NMR (CDCl₃, 126 MHz) δ 148.0,134.1, 129.9, 126.5, 122.8, 119.8, 65.3, 64.4, 55.3, 45.6, 32.1. MS(ESI) m/z: 297.0 [M+H]⁺ ([M+H]⁺ for C₁₉H₂₅N₂O requires 297.1).

P7C3-S140:1-amino-3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)propan-2-ol

5-(Oxiran-2-ylmethyl)-10,11-dihydro-5H-dibenzo[b,f]azepine (262 mg, 1.04mmol) was added to a 25 mL scintillation vial followed by NH₃-MeOH (7N,6.0 mL). The vial was heated to reflux for 12 h. Upon completion thereaction was cooled to room temperature and concentrated under reducedpressure to remove the remaining methanol. The crude residue waspurified by chromatography (SiO₂, 98:2 CH₂Cl₂/MeOH+1% NH₄OH) to affordthe desired product as an amorphous yellow foam (76.0 mg, 86%).

¹H NMR (CDCl₃, 500 MHz) δ 7.10-7.02 (m, 6H), 6.88 (m_(c), 2H), 3.76 (dd,1H, J=6.0, 12.1 Hz), 3.68 (brs, 1H), 3.63 (dd, 1H, J=6.2, 12.1 Hz), 3.31(brs, 2H), 3.11 (s, 4H), 2.78 (d, 1H, J=13.1 Hz), 2.55 (dd, 1H, J=7.3,13.1 Hz). ¹³C NMR (CDCl₃, 126 MHz) δ 148.1, 134.2, 130.1, 126.7, 123.1,120.0, 67.3, 67.2, 55.1, 53.6, 53.5, 32.2. MS (ESI) m/z: 269.0 [M+H]⁺([M+H]⁺ for C₁₇H₂₁N₂O requires 269.1).

P7C3-S143:1-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-3-(methylamino)propan-2-ol

Following the same procedure as for P7C3-S139, P7C3-S143 was preparedfrom 5-(oxiran-2-ylmethyl)-10,11-dihydro-5H-dibenzo[b,f]azepine (75.0mg, 0.30 mmol) and MeNH₂.HCl (30.4 mg, 0.45 mmol) with K₂CO₃ (125 mg,0.9 mmol) and isolated as a white solid (57.0 mg, 68%).

¹H NMR (CDCl₃, 500 MHz) δ 7.21-7.10 (m, 6H), 6.98 (m_(c), 2H), 3.98(brs, 1H), 3.91 (dd, 1H, J=5.7, 12.9 Hz), 3.84 (dd, 1H, J=7.2, 12.9 Hz),3.53 (dd, 1H, J=3.4, 9.6 Hz), 3.43 (dd, 1H, J=5.7, 9.6 Hz), 3.37 (s,3H), 3.20 (s, 4H), 2.51 (d, 1H, J=3.0 Hz).

¹³C NMR (CDCl₃, 126 MHz) δ 148.1, 134.3, 130.1, 126.7, 123.1, 120.0,75.0, 67.6, 59.4, 53.7, 32.2.

MS (ESI) m/z: 284.0 [M+H]⁺ ([M+H]⁺ for C₁₈H₂₃N₂O requires 283.1).

P7C3-S144:1-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-3-(isopropylamino)propan-2-ol

5-(Oxiran-2-ylmethyl)-10,11-dihydro-5H-dibenzo[b,f]azepine (100 mg, 0.4mmol) was added to a 25 mL scintillation vial followed by isopropanol (2mL) and isopropylamine (2 mL, 23.3 mmol). The vial was heated to refluxfor 12 h. Upon completion the reaction was cooled to room temperature,and the solvent was evaporated in vacuum. The crude residue wasrecrystallized (Hexanes/EtOAc) to give the desired product as a whitesolid (74.0 mg, 60%).

¹H NMR (CDCl₃, 500 MHz) δ 7.16-7.08 (m, 6H), 6.94 (m_(c), 2H), 3.86 (dd,1H, J=6.6, 11.9 Hz), 3.81 (brs, 1H), 3.74 (dd, 1H, J=5.0, 11.9 Hz), 3.18(s, 4H), 2.82 (dd, 1H, J=2.9, 11.9 Hz), 2.73 (m, 1H), 2.54 (dd, 1H,J=7.5, 11.9 Hz), 2.14 (brs, 1H), 1.01 (d, 6H, J=6.2 Hz). ¹³C NMR (CDCl₃,126 MHz) δ 148.2, 134.3, 130.1, 126.7, 123.1, 120.1, 67.2, 55.3, 50.1,49.0, 32.3, 23.2, 23.1. MS (ESI) m/z: 311.0 [M+H]⁺ ([M+H]⁺ for C₂₀H₂₇N₂Orequires 311.2).

P7C3-S145:1-(tert-butylamino)-3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)propan-2-ol

5-(Oxiran-2-ylmethyl)-10,11-dihydro-5H-dibenzo[b,f]azepine (100 mg, 0.4mmol) was added to a 25 mL scintillation vial followed by tert-butanol(1 mL) and tert-butylamine (3 mL, 28.5 mmol). The vial was heated toreflux for 12 h. Upon completion the reaction was cooled to roomtemperature, and the solvent was evaporated in vacuum. The crude residuewas purified by chromatography (SiO₂, 98:2 CH₂Cl₂/MeOH+1% NH₄OH) toafford the desired product as a white solid (123 mg, 95%).

¹H NMR (CDCl₃, 500 MHz) δ 7.18-7.07 (m, 6H), 6.95 (m_(c), 2H), 3.94 (dd,1H, J=6.0, 12.6 Hz), 3.76 (brs, 1H), 3.69 (dd, 1H, J=6.5, 12.6 Hz), 3.19(s, 4H), 2.79 (dd, 1H, J=2.7, 11.7 Hz), 2.50 (dd, 1H, J=7.9, 11.7 Hz),1.05 (s, 9H). ¹³C NMR (CDCl₃, 126 MHz) δ 148.3, 134.3, 130.0, 126.7,123.0, 120.1, 67.5, 55.3, 50.3, 46.2, 32.3, 29.2.

MS (ESI) m/z: 325.0 [M+H]⁺ ([M+H]⁺ for C₂₁H₂₉N₂O requires 325.2).

P7C3-S148:3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-fluoro-N,N-dimethylpropan-1-amine

An oven dried 20 mL scintillation vial containing1-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-3-(dimethylamino)propan-2-ol(47.0 mg, 0.16 mmol) was purged with N₂ and charged with anhydrousCH₂Cl₂ (9.0 mL, 0.018 M). The sealed vial was cooled in a dry iceacetone bath before the dropwise addition of morpholinosulfurtrifluoride (morpho-DAST, 39 μL, 0.32 mmol). The reaction temperaturewas maintained at 78° C. for an hour and then slowly warmed to roomtemperature and stirred overnight. The reaction was quenched withsaturated NaHCO₃ solution and diluted with CH₂Cl₂ and extracted threetimes. The combined organics were dried over Na₂SO₄, filtered andcondensed. The crude residue was purified by chromatography (SiO₂, 8:2Hexanes/EtOAc) to afford the desired product (12.3 mg, 26%).

¹H NMR (CDCl₃, 500 MHz) δ 7.187-7.08 (m, 6H), 6.94 (m_(c), 2H),4.81-4.64 (m, 1H), 4.00 (d, 1H, J=6.0 Hz), 3.97 (t, 1H, J=5.6 Hz), 3.17(s, 4H), 2.64-2.56 (m, 1H), 2.56-2.52 (m, 1H), 2.23 (s, 6H). ¹³C NMR(CDCl₃, 126 MHz) δ 147.9, 134.7, 130.1, 126.7, 123.1, 120.2, 90.5, 88.7,62.1 (d, J=20.6 Hz), 53.9 (d, J=25.8 Hz), 46.3, 32.1. MS (ESI) m/z:299.0 [M+H]⁺ ([M+H]⁺ for C₁₉H₂₄FN₂ requires 299.1).

P7C3-S149:1-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-3-fluoro-N,N-dimethylpropan-2-amine

1-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-3-fluoro-N,N-dimethylpropan-2-aminewas obtained as main product in the synthesis of (P7C3-S148) (28.5 mg,60%).

¹H NMR (CDCl₃, 500 MHz) δ 7.17-7.08 (m, 6H), 6.95 (m_(c), 2H), 4.61 (dd,2H, J=3.7, 47.8 Hz), 4.09 (dt, 1H, J=3.3, 12.5 Hz), 3.62 (m, 1H), 3.16(s, 4H), 2.94 (ddd, 1H, J=4.3, 9.4, 25.6 Hz), 2.42 (s, 6H). ¹³C NMR(CDCl₃, 126 MHz) δ 148.3, 134.4, 130.2, 126.7, 123.0, 119.8, 61.0, 60.9,48.4, 42.0, 32.2. MS (ESI) m/z: 299.0 [M+H]⁺ ([M+H]⁺ for C₁₉H₂₄FN₂requires 299.1).

P7C3-S152:3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-fluoro-N-methylpropan-1-amineStep 1. Synthesis ofN-(3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-hydroxypropyl)-N-methyl-4-nitrobenzenesulfonamide

A heterogeneous mixture of N-methyl-4-nitrobenzenesulfonamide (95.0 mg,0.44 mmol) (synthesized following a reported procedure: Harshani R. L.;Kazi, A; Ge, Y; Guida, W. C.; Sebti, S.; Luo, Y.; Kendig, R.; Jain, S.;Daniel, K.; Santiago, D., Bioorg. Med. Chem. 2010, 18, 5576-5592) intoluene (3.4 mL, 0.13 M) under a N₂ atmosphere was cooled in a dryice/acetone bath before dropwise addition of n-BuLi (0.240 mL of 2.5 Min hexanes, 0.60 mmol). The reaction was stirred at 78° C. for 20minutes before addition of5-(oxiran-2-ylmethyl)-10,11-dihydro-5H-dibenzo[b,f]azepine (100 mg, 0.4mmol). The heterogeneous mixture was stirred at room temperature for 5min before heating at 100° C. for 72 h. The cooled reaction was dilutedwith EtOAc and washed 3×5% acetic acid solution, followed by a brinewash. The organic layer was dried over Na₂SO₄, filtered and condensed.The crude residue was purified by chromatography (SiO₂, 7:3Hexanes/EtOAc) to afford the desired product (45.0 mg, 25%).

¹H NMR (CDCl₃, 500 MHz) δ 8.32 (d, 2H, J=8.6 Hz), 7.90 (d, 2H, J=8.6Hz), 7.20-7.07 (m, 6H), 6.98 (m_(c), 2H), 3.99-3.91 (m, 2H), 3.75(m_(c), 1H), 3.34-3.27 (m, 1H), 3.16 (s, 4H), 2.85 (s, 3H). ¹³C NMR(CDCl₃, 126 MHz) δ 147.8, 134.2, 130.3, 128.6, 126.9, 124.5, 123.6,119.9, 63.3, 54.5, 54.3, 37.0, 32.2. MS (ESI) m/z: 467.9 [M+H]⁺ ([M+H]⁺for C₂₄H₂₆N₃O₅S requires 468.1).

Step 2. Synthesis ofN-(3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-fluoropropyl)-N-methyl-4-nitrobenzenesulfonamide

This intermediate was prepared analogously to P7C3-S148. The crudeproduct was carried forward without further purification.

¹H NMR (CDCl₃, 500 MHz) δ 8.24 (d, 2H, J=8.8 Hz), 7.77 (d, 2H, J=8.8Hz), 7.20-7.05 (m, 6H), 7.01 (m_(c), 2H), 4.76-4.55 (m, 1H), 4.10 (td,1H, J=5.8, 13.4 Hz), 3.87 (td, 1H, J=6.6, 13.9, 14.8 Hz), 3.78-3.60 (m,2H), 3.20 (s, 4H), 2.87 (s, 3H). ¹³C NMR (CDCl₃, 126 MHz) δ 147.6,134.8, 130.4, 128.4, 126.8, 124.5, 123.6, 119.9, 91.0, 89.2, 67.0, 52.7(dd, J=23.7, 32.1 Hz), 44.4, 36.5, 32.0. MS (ESI) m/z: 469.9 [M+H]⁺([M+H]⁺ for C₂₄H₂₅FN₃O₄S requires 470.1).

Step 3. Synthesis of3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-fluoro-N-methylpropan-1-amine(P7C3-S152)

To a vial containingN-(3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-2-fluoropropyl)-N-methyl-4-nitrobenzenesulfonamide(53.2 mg, 0.113 mmol) was added lithium hydroxide (12.2 mg, 0.510 mmol),DMF (2.0 mL, 0.06 M) and mercaptoacetic acid (16.0 μL, 0.227 mmol).After stirring at room temperature for 1 h the reaction mixture wasdiluted with EtOAc and washed sequentially with H₂O, saturated aqueousNaHCO₃, H₂O (3×) and brine. The organic layer was dried over Na₂SO₄,filtered and condensed. The crude residue was purified by chromatography(SiO₂, 98:2 CH₂Cl₂/MeOH+1% Et₃N) to afford the desired product (14.5 mg,47%).

¹H NMR (CDCl₃, 500 MHz) δ 7.09-6.95 (m, 6H), 6.86 (m_(c), 2H), 4.77-4.55(m, 1H), 3.97 (td, 1H, J=6.6, 13.8 Hz), 3.85 (m_(c), 1H), 3.07 (s, 4H),2.82-2.75 (m, 1H), 2.74-2.68 (m, 1H), 2.31 (s, 3H). ¹³C NMR (CDCl₃, 126MHz) δ 147.6, 134.5, 130.0, 126.6, 123.2, 119.9, 90.4, 88.7, 53.3 (dd,J=22.7, 46.9 Hz), 49.0 (dp, J=21.4, 42.9 Hz), 35.6, 31.9.

MS (ESI) m/z: 285.0 [M+H]⁺ ([M+H]⁺ for C₁₈H₂₂FN₂ requires 285.1).

P7C3-S158:1-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-3-((3-methoxyphenyl)amino)propan-2-ol

Following the same procedure as for P7C3-S135, P7C3-S158 was preparedfrom iminodibenzyl (68.2 g, 0.35 mmol) and3-methoxy-N-(oxiran-2-ylmethyl)aniline (75.1 mg, 0.42 mmol) with n-BuLi(0.167 mL of 2.5 M in hexanes, 0.42 mmol) in dry THF (1 mL) and isolatedafter chromatography (SiO₂, 7:3 Hexanes/EtOAc) (10.5 mg, 8%).

¹H NMR (CDCl₃, 400 MHz) δ 7.17-7.09 (m, 6H), 7.04 (m_(c), 2H), 7.00-6.94(m, 2H), 6.30 (dd, 1H, J=2.3, 8.2 Hz), 6.22-6.15 (m, 2H), 4.07 (m_(c),1H), 3.94 (dd, 1H, J=4.9, 13.0 Hz), 3.82 (dd, 1H, J=8.0, 13.0 Hz), 3.74(s, 3H), 3.38 (dd, 1H, J=3.4, 12.8 Hz), 3.20 (s, 4H), 3.12 (dd, 1H,J=7.0, 12.8 Hz). ¹³C NMR (CDCl₃, 126 MHz) δ 148.0, 134.3, 130.3, 130.2,126.8, 123.5, 119.9, 106.6, 103.7, 99.5, 67.1, 55.2, 54.9, 48.2, 32.3.

MS (ESI) m/z: 375.0 [M+H]⁺ ([M+H]⁺ for C₂₄H₂₇N₂O₂ requires 375.2).

P7C3-S162: 3,6-dibromo-9H-carbazole

This analog was purchased from SigmaAldrich

P7C3-S163: 3,6-dibromo-9-methyl-9H-carbazole

The title compound was prepared from P7C3-S162 by methylation with NaHand methyl iodide.

The ¹H NMR data was consistent with that reported in Eur. J. Med. Chem.1997 (32) 781.

P7C3-S164: ethyl 2-(3,6-dibromo-9H-carbazol-9-yl)acetate

Sodium Hydride was added to a stirred solution of 3,6-dibromocarbazole(250 mg, 0.77 mmol) in DMF (4 ml). The solution was stirred for 30minutes before the dropwise addition of ethyl chloroacetate. After 12hours water was added and a fine white precipitate formed which wasfiltered and rinsed with water and hexanes to afford the desired ethylester in 93% yield.

¹H NMR (500 MHz, CDCl₃) δ 8.15 (s, 2H), 7.56 (d, J=8.6 Hz, 2H), 7.21 (d,J=8.5 Hz, 2H), 4.94 (s, 2H), 4.20 (q, J=6.3 Hz, 2H), 1.26-1.18 (m, 3H).ESI m/z: 409.7 ([M+H]⁺, C₁₆H₁₃Br₂NO₂ requires 409.9)

P7C3-S165: 2-(3,6-dibromo-9H-carbazol-9-yl)acetic acid

Ethyl 2-(3,6-dibromo-9H-carbazol-9-yl)acetate (50 mg, 0.12 mmol) wasdissolved in 0.6 ml of THF. To this stirred solution was added 0.4 ml ofmethanol, 0.2 ml of water, and lithium hydroxide (14.5 mg, 0.6 mmol).After 1 hour all starting material had been consumed. The solution wasacidified with 1N HCl. Upon reaching a pH of about 4 precipitate hadformed which was collected and rinsed with fresh water to afford thedesired acid in 95% yield.

¹H NMR (500 MHz, Acetone-d₆) δ 8.41 (s, 2H), 7.62 (dt, J=8.6, 1.7 Hz,2H), 7.58 (dd, J=8.7, 1.5 Hz, 2H), 5.31 (d, J=1.6 Hz, 2H). ESI m/z:381.7 ([M+H]⁺, C₁₄H₉Br₂NO₂ requires 381.9)

P7C3-S169: 1-(3,6-dibromo-9H-carbazol-9-yl)-2-methylpropan-2-ol

A flask was charged with ethyl 2-(3,6-dibromo-9H-carbazol-9-yl)acetate(100 mg, 0.243 mmol) and purged with nitrogen gas. Anhydrous THF (2 ml)was added and the solution was cooled to −78° C. in a dry ice/acetonebath. Methyl magnesium bromide (0.19 mL of a 3M ether solution) wasadded drop wise. The reaction was warmed to room temperature and stirredovernight. Upon completion the reaction was cooled to 0° C. and NH₄Cl(sat.) was added. The mixture was extracted with ethyl acetate, washedwith water, brine and dried over magnesium sulfate. The crude mixturewas purified on SiO₂ (10% EtOAc/hexanes. Isolated yield was 69%.

¹H NMR (500 MHz, CDCl₃) δ 8.14 (s, 2H), 7.55 (d, J=8.7 Hz, 2H), 7.41 (d,J=8.7 Hz, 2H), 4.24 (s, 2H), 1.35 (s, 6H). ESI m/z: 439.95 ([M+HCOO]⁻,C₁₆H₁₅Br₂NO requires 394.95)

P7C3-S170: 1,3-bis(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)propan-2-ol

P7C3-S170 was obtained as a by-product in the synthesis of5-(oxiran-2-ylmethyl)-10,11-dihydro-5H-dibenzo[b,f]azepine and isolatedas a white solid (74.7 mg, 33%).

¹H NMR (CDCl₃, 500 MHz) δ 7.14 (d, 4H, J=7.3 Hz), 7.03 (d, 4H, J=7.1Hz), 6.99-6.84 (m, 8H), 4.10 (m_(c), 1H), 3.97 (dd, 2H, J=5.3, 12.9 Hz),3.79 (dd, 2H, J=7.2, 12.9 Hz), 3.24 (m_(c), 8H). ¹³C NMR (CDCl₃, 126MHz) δ 148.0, 134.1, 130.1, 126.7, 123.1, 119.7, 65.4, 55.2, 32.3. MS(ESI) m/z: 447.0 [M+H]⁺ ([M+H]⁺ for C₃₁H₃₁N₂O requires 447.2).

P7C3-S171: 2-(3,6-dibromo-9H-carbazol-9-yl)ethanol

Ethyl 2-(3,6-dibromo-9H-carbazol-9-yl)acetate (50 mg, 0.12 mmol) wasdissolved in 1 ml of THF. LiBH₄ (5.3 mg, 0.24 mmol) was added, and themixture was heated to 60° C. for 45 minutes. The reaction was cooled toroom temperature and 10% NaHCO₃ was added. This material was extractedwith EtOAc, washed with 1N HCl, H₂O, and brine. The crude material didnot require further purification.

¹H NMR (500 MHz, CDCl₃) δ 8.15 (s, 2H), 7.56 (d, J=8.7 Hz, 2H), 7.35 (d,J=8.7 Hz, 2H), 4.44 (t, J=4.8 Hz, 2H), 4.05 (t, J=4.8 Hz, 2H). ESI m/z:367.7 ([M+H]⁺, C₁₄H₁₁Br₂NO requires 367.92)

P7C3-S185:1-(naphthalen-1-ylamino)-3-(2-phenyl-1H-indol-1-yl)propan-2-ol

The title compound was synthesized according to Asso et al., Chem MedChem, 2008, (3) 1530.

P7C3-S189: 9-(3-azido-2-fluoropropyl)-3,6-dibromo-9H-carbazole

The title compound was prepared by opening3,6-dibromo-9-(oxiran-2-ylmethyl)-9H-carbazole with NaN₃ in ethanol,followed by fluorination according to Representative Procedure 4.

MS (ESI) m/z: 468.6, [M+formate]−, C₁₅H₁₁Br₂FN₄ requires 423.9

P7C3-S193: Melatonin

This compound was purchased from SigmaAldrich.

P7C3-S199: Vinpocetine

This compound was purchased from SigmaAldrich

P7C3-S200: PK 11195

This compound was purchased from SigmaAldrich

P7C3-S201: N,N-Dihexyl-2-(4-fluorophenyl)indole-3-acetamide, also knownas FGIN-1-27

This compound was purchased from SigmaAldrich.

P7C3-S203: 4′-chlorodiazepam

This compound was purchased from SigmaAldrich.

P7C3-S207: 5-bromo-DL-tryptophan

This compound was purchased from SigmaAldrich.

P7C3-S206: 6-bromo-9H-pyrido[3,4-b]indole-3-carboxylic acid

Ethyl 6-bromo-9H-pyrido[3,4-b]indole-3-carboxylate was suspended in 10%NaOH_((aq.)) and heated to reflux for 3 hours. Upon completion thereaction was cooled to room temperature and acidified with ice coldHCl_((conc.)). The temperature was maintained at 0° C. and stirred for 1hour. The precipitate was filtered, rinsed with water, and dried undervacuum to afford the desired compound in 91% yield.

¹H NMR (500 MHz, DMSO-d₆) δ 12.92 (s, 1H), 9.30 (s, 1H), 9.18 (s, 1H),8.90 (s, 1H), 7.87 (d, J=8.7 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H). ESI m/z:290.8 ([M+H]⁺, C₁₂H₇BrN₂O₂ requires 290.97)

P7C3-S209: Synthesis of 3-bromo-6-methoxy-9H-carbazole

3-Methoxy-9H-carbazole (Bedford, R. B.; Betham, M. J. Org. Chem. 2006,71, 9403-9410) (0.029 g, 0.147 mmol) was dissolved in dry DMF (0.28 mL)and NBS (0.026 g, 0.147 mmol) was added to the solution. The reactionmixture was stirred at room temperature for 2 h under absence of light.The solution was poured into water (2 mL), filtered and washed withwater. The title compound was isolated as a grey solid (0.033 g, 82%).

¹H NMR (CDCl₃, 400 MHz) δ 8.13 (s, 1H), 7.91 (brs, 1H), 7.50-7.43 (m,2H), 7.30 (d, 1H, J=8.7 Hz), 7.25 (d, 1H, J=5.6 Hz), 7.08 (d, 1H, J=8.7Hz), 3.91 (s, 3H). MS (ESI) m/z 276.9 [M+H]⁺ ([M+H]⁺, C₁₃H₁₁BrNOrequires 276.0).

P7C3-S210: 2-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)acetic acid

P7C3-S210 was prepared analogously to P7C3-S165 (276 mg, 85%).

¹H NMR (CDCl₃, 500 MHz) δ 7.15-7.09 (m, 4H), 7.03 (d, 2H, J=7.9 Hz),6.96 (t, 2H, J=7.3 Hz), 4.58 (s, 2H), 3.21 (s, 4H). ¹³C NMR (CDCl₃, 126MHz) δ 175.5, 147.5, 134.5, 130.2, 126.8, 123.4, 119.6, 54.6, 32.6. MS(ESI) m/z: 254.0 [M+H]⁺ ([M+H]⁺ for C₁₆H₁₆NO₂ requires 254.1).

P7C3-S211: 2-(3,6-dibromo-9H-carbazol-9-yl)propanoic acid Step 1: ethyl2-(3,6-dibromo-9H-carbazol-9-yl)propanoate

Synthesized analogously to P7C3-S164.

¹H NMR (500 MHz, CDCl₃) δ 8.15 (d, J=1.8 Hz, 2H), 7.54 (dd, J=8.7, 1.9Hz, 2H), 7.26 (d, J=8.7 Hz, 2H), 5.31 (q, J=7.3 Hz, 1H), 4.17 (q, J=7.1Hz, 2H), 1.80 (d, J=7.3 Hz, 3H), 1.12 (t, J=7.1 Hz, 3H). ESI m/z: 423.7([M+H]⁺, C₁₇H₁₅Br₂NO₂ requires 423.95)

Step 2: P7C3-S211: 2-(3,6-dibromo-9H-carbazol-9-yl)propanoic acid

Synthesized analogously to P7C3-S165.

¹H NMR (400 MHz, CDCL₃) δ 8.16 (d, J=1.8 Hz, 2H), 7.55 (dd, J=8.7, 1.8Hz, 2H), 7.27 (s, 2H), 5.39 (dd, J=14.7, 7.3 Hz, 1H), 1.85 (d, J=7.3 Hz,3H). ESI m/z: 395.7 ([M+H]⁺, C₁₅H₂₁Br₂NO₂ requires 395.92)

P7C3-S212: iminodibenzyl

This compound was purchased from SigmaAldrich.

P7C3-S216: 6-bromo-9H-carbazole-3-carbonitrile Step 1:9-H-carbazole-3-carbonitrile

3-bromo-9H-carbazole (150 mg, 0.61 mmol) and CuCN (60 mg, 0.67 mmol)were dissolved in 3 ml of NMP and heated to 200° C. overnight. Uponcompletion the reaction was warmed to room temperature, diluted with 3ml of H₂O and filtered to remove CuBr salts. The filtrate was extracted3× with EtOAc, washed with H₂O, brine, and dried over MgSO₄. The crudemixture was purified on SiO₂ (0 to 50% EtOAc/hexanes to afford9-H-carbazole-3-carbonitrile.

¹H NMR (500 MHz, DMSO-d₆) δ 11.87 (s, 1H), 8.71 (s, 1H), 8.24 (d, J=7.8Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.57 (d, J=7.9Hz, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.26 (t, J=7.5 Hz, 1H). ESI m/z: 193.0([M+H]⁺, C₁₃H₈N₂ requires 193.07)

Step 2: 6-bromo-9H-carbazole-3-carbonitrile (P7C3-S216)

9-H-carbazole-3-carbonitrile (185 mg, 0.962 mmol) and N-bromosuccinimide(171 mg, 0.92 mmol) were added to 5 ml of EtOAc and 13 ml of toluene.This mixture was stirred for 3 days at room temperature. Upon completionof the reaction, the reaction was concentrated, diluted in EtOAc, washedwith NaHCO₃, H₂O, brine, and dried over Na₂SO₄. The crude mixture waspurified on SiO₂ (0 to 50% EtOAc/hexanes to afford the desired productin 90% yield.

¹H NMR (400 MHz, CDCl₃) δ 8.38 (s, 1H), 8.35 (s, 1H), 8.22 (s, 1H), 7.69(dd, J=8.5, 1.4 Hz, 1H), 7.60 (dd, J=8.6, 1.8 Hz, 1H), 7.50 (d, J=8.5Hz, 1H), 7.38 (d, J=8.6 Hz, 1H). ESI m/z: 270.9 ([M+H]⁺, C₁₃H₇BrN₂requires 270.98)

P7C3-S222: 3-amino-5-bromo-1H-indole-2-carbonitrile Step 1. Synthesis of5-bromo-2-((cyanomethyl)amino)benzonitrile

Following Representative Procedure 1,2-((cyanomethyl)amino)benzonitrile(Michaelidou, S. S.; Koutentis, P. A. Tetrahedron 2010, 66, 685-688)(0.020 g, 0.127 mmol) was treated with NBS (0.034 g, 0.191 mmol) inCH₂Cl₂:MeOH (1:1) (25 mL) to afford the title product (0.017 g, 58%). ¹HNMR (CDCl₃-MeOD [4:2], 500 MHz) δ 7.59-7.54 (m, 2H), 6.67 (d, 1H, J=8.8Hz). 4.16 (s, 2H). MS (ESI) m/z 235.8 [M−H]⁻ ([M−H]⁻, C₉H₅BrN₃ requires235.0).

Step 2. Synthesis of 3-amino-5-bromo-1H-indole-2-carbonitrile(P7C3-S222)

Following a literature procedure (Michaelidou, S. S.; Koutentis, P. A.Tetrahedron 2010, 66, 685-688),5-bromo-2-((cyanomethyl)amino)benzonitrile (0.290 g, 1.234 mmol) andK₂CO₃ (0.085 g, 0.617 mmol) were dissolved in EtOH (3.9 mL) and heatedto 120° C. in a microwave reactor for 10 min. The reaction mixture wasthen cooled to room temperature, diluted with water and extracted withCH₂Cl₂. The organic layers were dried over Na₂SO₄, filtered andcondensed. The crude mixture was purified by chromatography (SiO₂, O-50%EtOAc/Hexanes) to afford the title compound (0.254 g, 88%).

¹H NMR (CDCl₃-MeOD [4:2], 500 MHz) δ 7.46 (d, 1H, J=1.7 Hz), 7.04 (dd,1H, J=1.7, 8.8 Hz), 6.83 (d, 1H, J=8.8 Hz). MS (ESI) m/z 236.8 [M+H]⁺([M+H]⁺, C₉H₇BrN₃ requires 237.0).

P7C3-S224: 2-(3-bromo-6-cyano-9H-carbazol-9-yl)acetic acid

The title compound was prepared analogously to P7C3-S165.

¹H NMR (CDCl₃₊ (CD₃)₂CO, 400 MHz) δ 8.18 (d, J=1.6 Hz, 1H), 8.04 (d,J=1.9 Hz, 1H), 7.51 (dd, J=8.5, 1.6 Hz, 1H), 7.40 (dd, J=8.6, 1.9 Hz,1H), 7.31 (d, J=8.6 Hz, 1H), 7.17 (d, J=8.7 Hz, 1H), 4.91 (s, 2H). MS(ESI), m/z: calculated 327.98. Found 328.8 (M+1).

P7C3-S225: 6-bromo-9H-carbazole-3-carboxylic acid

P7C3-S216 (299.6 mg, 1.1 mmol) was treated with HCl in dioxane (4.0 M, 3ml) and concentrated HCl at 100° C. for 60 hours. The crude mixture wastaken up in EtOAc, neutralized with 1N NaOH and washed with brine. Theorganic layer was dried over Na₂SO₄, filtered and condensed. Columnchromatography in 5% MeOH/DCM (+0.1% formic acid) gave desired in 90%yield.

¹H NMR (DMSO, 400 MHz) δ δ 11.69 (s, 1H), 8.75 (d, J=1.6 Hz, 1H), 8.33(d, J=1.9 Hz, 1H), 7.98 (dd, J=8.5, 1.7 Hz, 1H), 7.89 (bs, 1H),7.62-7.42 (m, 2H), 7.24 (bs, 1H). MS (ESI), m/z: calculated 288.97.Found 289.8 (M+1).

P7C3-S227: 6-bromo-9-(carboxymethyl)-9H-pyrido[3,4-b]indole-3-carboxylicacid Step 1: ethyl6-bromo-9-(2-ethoxy-2-oxoethyl)-9H-pyrido[3,4-b]indole-3-carboxylate

Ethyl6-bromo-9-(2-ethoxy-2-oxoethyl)-9H-pyrido[3,4-b]indole-3-carboxylate wassynthesized analogously to P7C3-S164. The crude material was purified onSiO₂ (0-60% EtOAc/hexanes to give the desired compound in 92% yield.

¹H NMR (500 MHz, DMSO-d₆) δ 9.13 (s, 1H), 9.03 (s, 1H), 8.78 (s, 1H),7.80 (dd, J=8.8, 1.5 Hz, 1H), 7.74 (d, J=8.9 Hz, 1H), 5.59 (s, 2H), 4.39(q, J=7.1 Hz, 2H), 4.21-4.12 (m, 2H), 1.38 (t, J=7.1 Hz, 3H), 1.21 (t,J=7.1 Hz, 3H). ESI m/z: 404.8 ([M+H]⁺, C₁₂H₁₇BrN₂O₄ requires 405.04)

Step 2:—6-bromo-9-(carboxymethyl)-9H-pyrido[3,4-b]indole-3-carboxylicacid

6-bromo-9-(carboxymethyl)-9H-pyrido[3,4-b]indole-3-carboxylic acid(P7C3-S227) was synthesized analogously to P7C3-S165.

¹H NMR (500 MHz, DMSO-d₆) δ 9.13 (s, 1H), 9.02 (s, 1H), 8.75 (s, 1H),7.80 (d, J=9.2 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 5.49 (s, 2H). ESI m/z:348.7 ([M+H]⁺, C₁₄H₉BrN₂O₄ requires 348.97)

P7C3-S228: 3-bromo-6-methyl-9H-carbazole

This compound was prepared according to U.S. Pat. No. 6,018,046 A1,incorporated herein by reference in its entirety.

P7C3-S229: 1-(9H-carbazol-9-yl)-3-(phenylamino)propan-2-ol

The title compound was prepared according to the procedure of Asso etal, Chem Med Chem, 2008 (3) 1530.

MS (ESI): 317.1 [M+H]⁺, C₂₁H₂₀N₂O requires 316.2.

P7C3-S230—2-(3,6-dibromo-9H-carbazol-9-yl)-N-(phenylsulfonyl)acetamide

2-(3,6-dibromo-9H-carbazol-9-yl)-N-(phenylsulfonyl)acetamide wassynthesized analogously to P7C3-S232 except benzensulfonamide was used.

¹H NMR (400 MHz, Acetone-d₆) δ 8.37 (d, J=1.8 Hz, 2H), 8.00 (dd, J=8.4,1.2 Hz, 2H), 7.75-7.69 (m, 1H), 7.63-7.57 (m, 2H), 7.53 (dd, J=8.7, 2.0Hz, 2H), 7.38 (d, J=8.7 Hz, 2H), 5.33 (s, 2H). ESI m/z: 518.5 ([M−H]⁺,C₂₀H₁₄Br₂N₂O₃S requires 518.91)

P7C3-S231—2-(3,6-dibromo-9H-carbazol-9-yl)-N-hydroxyacetamide

Following a published procedure (J. Med. Chem., 2011, 54, 5576-5582),ethyl 2-(3,6-dibromo-9H-carbazol-9-yl)acetate (P7C3-S164) (50 mg, 0.12mmol) was suspended in a 1:1 (v/v) mixture of methanol (500 ul) and 50%hydroxylamine (aq.). To this suspension was added 1 N NaOH_((aq)) (250ul). Upon completion 1N HCl was added, upon which the productprecipitated from solution. The precipitate was further purified on SiO₂(0-60% EtOAc/hexanes.)

¹H NMR (500 MHz, Acetone-d₆) δ 8.39 (s, 2H), 7.59 (dd, J=25.4, 8.4 Hz,4H), 5.08 (s, 2H). ESI m/z: 394.5 ([M−H]⁺, C₁₄H₁₀Br₂N₂O₂ requires394.91)

P7C3-S232: 2-(3,6-dibromo-9H-carbazol-9-yl)-N-(methylsulfonyl)acetamide

Following a published procedure (Bioorg. Med. Chem., 2006, 1331-1338) asolution of 2-(3,6-dibromo-9H-carbazol-9-yl)acetic acid (P7C3-S165) (100mg, 0.26 mmol) in dry THF was added to a stirred solution ofcarbonyldiimidazole (42.3 mg, 0.261 mmol) in THF. The mixture wasstirred 30 min at room temperature and 30 min at reflux. The mixture wascooled to room temperature and methanesulfonamide (25 mg, 0.261 mmol)was added in one portion and stirred for 10 minutes. A solution of1,8-Diazabicyclo[5.4.0]undec-7-ene (40 mg, 0.261 mmol) in THF was addeddropwise. The solution was stirred overnight at room temperature. Thesolution was poured into ice cold 1 N HCl and extracted with EtOAc. Theorganic layer was washed with water, brine, dried over MgSO₄ andconcentrated. The crude material was purified on SiO₂ (0-50%EtOAc/hexanes.)

¹H NMR (500 MHz, Acetone-d₆) δ 8.39 (s, 2H), 7.57 (dd, J=22.2, 8.7 Hz,4H), 5.22 (s, 2H), 3.11 (s, 3H) ESI m/z: 458.5 ([M−H]⁺, C₁₅H₁₂Br₂N₂O₃Srequires 456.89)

P7C3-S235: 2-(3,6-dibromo-9H-carbazol-9-yl)acetonitrile

3,6-dibromocarbazole (500 mg, 1.54 mmol) was dissolved in DMF (7.5 ml)and treated with KOH (86 mg, 1.54 mmol) for 30 minutes. K₂CO₃ (319 mg,2.3 mmol) and bromoacetonitrile (332 mg, 2.77 mmol) were added. Thereaction was stirred overnight at room temperature. Upon addition of H₂Oa precipitate formed which was filtered and purified on SiO₂ (0-25%EtOAc/hexanes.)

¹H NMR (500 MHz, Acetone-d₆) δ 8.47 (s, 2H), 7.74 (dd, J=20.1, 8.7 Hz,4H), 5.73 (s, 2H). ESI m/z: 360.6 ([M−H]⁺, C₁₄H₈Br₂N₂ requires 360.91)

P7C3-S236: 3-bromo-9H-carbazole

This compound was purchased from SigmaAldrich.

P7C3-S237: 3,6-dimethyl-9H-carbazole

This compound was prepared as reported in Beyer, M. et al. J. Org. Chem.2003 (68) 2209.

P7C3-S238: 2-(3-bromo-6-carbamoyl-9H-carbazol-9-yl)acetic acid

The title compound was prepared analogously to P7C3-S165.

MS (ESI) m/z: 346.9 [M+H]⁺, C15H11BrN2O3 requires 346.0

P7C3-S239: 6-bromo-9-(carboxymethyl)-9H-carbazole-3-carboxylic acid

The title compound was prepared analogously to P7C3-165

¹H NMR (DMSO, 500 MHz) δ 13.16 (s, 1H), 8.78 (s, 1H), 8.38 (s, 1H), 8.02(d, J=8.6 Hz, 1H), 7.93 (s, 1H), 7.62 (d, J=15.0 Hz, 2H), 7.29 (s, 1H),5.29 (s, 2H). MS (ESI), m/z: calculated 346.98. Found 347.9 (M+1).

P7C3-S240: 2-(3-bromo-6-methyl-9H-carbazol-9-yl)acetic acid

The title compound was prepared analogously to P7C3-165.

¹H NMR (CDCl₃+(CD₃)₂CO, 400) δ 8.09 (d, J=2.0 Hz, 1H), 7.79 (s, 1H),7.54 (d, J=8.6 Hz, 2H), 7.43 (dd, J=8.7, 2.0 Hz, 1H), 7.26 (m, 1H), 4.99(s, 2H), 2.44 (s, 3H). MS (ESI), m/z: calculated 317.01. Found 318.0(M+1).

P7C3-S241:N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-1,1,1-trifluoro-N-(3-methoxyphenyl)methanesulfonamide

Following Representative Procedure 4, P7C3-S244 was fluorinated to givethe title compound. ¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, J=1.9 Hz, 2H),7.56 (dd, J=8.7, 1.9 Hz, 2H), 7.32 (t, J=8.2 Hz, 1H), 7.21 (d, J=8.6 Hz,2H), 6.99-6.90 (m, 2H), 6.86 (m, 1H), 5.08-4.86 (dm, 1H), 4.57-4.44 (m,2H), 4.09 (m, 2H), 3.79 (s, 3H). MS (ESI), m/z: calculated 635.93. Found680.6 (M+HCOO⁻)⁻.

P7C3-S242: 3-indolepropionic acid

This compound was purchased from SigmaAldrich.

P7C3-S244:N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-1,1,1-trifluoro-N-(3-methoxyphenyl)methanesulfonamideStep 1: 1,1,1-trifluoro-N-(3-methoxyphenyl)methanesulfonamide

A solution of trifluoromethanesulfonic anhydride (45 ml, 26.7 mmol) inmethylene chloride (250 ml) was added dropwise to an ice chilledsolution of m-anisidine (25 ml, 22.3 mmol) and triethylamine (39 ml,28.0 mmol) in methylene chloride (1.25 L). The reaction was stirredovernight at ambient temperature. Workup was performed portionwise. Eachof the two portions was basified by addition of 250 ml of 2.5 N NaOHsolution and 625 ml MeOH. The aqueous was extracted thrice (100 ml each)with methylene chloride. The combined aqueous phases was acidified to pH2 with 18% HCl and again extracted with methylene chloride three times.The organic layer is dried over MgSO₄, filtered and condensed to give17.69 g of brown solid in 77% yield.

¹H NMR (CDCl₃, 400 MHz) δ7.48-7.13 (m, 1H), 6.97-6.61 (m, 3H), 3.82 (s,3H). MS (ESI), m/z: calculated 255.21. Found 255.9 (M+1)⁺.

Step 2:N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-1,1,1-trifluoro-N-(3-methoxyphenyl)methanesulfonamide(P7C3-S244)

N-butyllithium (2.5 M in hexanes, 48 ml) was added dropwise to anice-cooled solution of1,1,1-trifluoro-N-(3-methoxyphenyl)methanesulfonamide (22.07 g, 86.5mmol) in dry dioxane (145 ml) over a 40 minute period. The solution wasthen stirred at ambient temperature for 15 minutes before addition of3,6-dibromo-9-(oxiran-2-ylmethyl)-9H-carbazole (25.05 g, 65.7 mmol)followed by heating at 90° C. for an hour. The reaction was cooled thendiluted with 1.2 L ethyl acetate and washed several times with water andfinally brine. The organic layer was dried over MgSO₄, filtered andcondensed to give an orange viscous mixture. The residue was dissolvedin 150 ml of 60% methylene chloride/hexanes, then concentrated to yellowfoam to which a further 150 ml of 60% methylene chloride/hexanes wasadded and stirred overnight. The mixture was filtered and washed severaltimes with 60% methylene chloride/hexanes until the solid was whitegiving 20.1 g of 99%

¹H NMR (CDCl₃, 400 MHz) δ 8.13 (d, J=1.9 Hz, 2H), 7.54 (dd, J=8.7, 1.9Hz, 2H), 7.33 (t, J=8.1 Hz, 1H), 7.22 (d, J=8.7 Hz, 2H), 6.95 (dd,J=8.4, 2.3 Hz, 2H), 6.88 (s, 1H), 4.56-4.10 (m, 4H), 3.99 (m, 1H), 3.81(s, 3H), 1.98 (d, J=4.2 Hz, 1H). MS (ESI), m/z: calculated 633.94. Found678.6 (M+HCOO)⁻.

P7C3-S246: ethyl 5-tosyl-5H-pyrimido[5,4-b]indole-2-carboxylate

The title compound was synthesized following a reported procedure (Rahtzet al. U.S. Pat. No. 4,564,610 A1).

¹H NMR (CDCl₃, 500 MHz) δ 9.76 (s, 1H), 8.44 (d, 1H, J=7.7 Hz), 8.37 (d,1H, J=8.5 Hz), 7.80 (t, 1H, J=7.9 Hz), 7.75 (d, 2H, J=8.4 Hz), 7.54 (t,1H, J=7.5 Hz), 7.18 (d, 2H, J=8.1 Hz), 4.60 (q, 2H, J=7.1 Hz), 2.31 (s,3H), 1.52 (t, 3H, J=7.1 Hz).

P7C3-S245: 2-(dimethylamino)-5H-pyrimido[5,4-b]indol-4-ol

To a suspension of 3-amino-1H-indole-2-carbonitrile (Michaelidou, S. S.;Koutentis, P. A. Tetrahedron 2010, 66, 685-688) (0.032 g, 0.200 mmol) inDCE (1.5 mL) was added Cl₂CN⁺Me₂Cl⁻ (0.046 g, 0.28 mmol) and the mixturewas stirred under reflux overnight. Upon completion, the cooled reactionwas concentrated and dissolved in AcOH (0.6 mL). Then, NH₄OAc (0.040 g,0.52 mmol) was added and the mixture was stirred under reflux for 20 h.The cooled reaction was neutralized with saturated NaHCO₃ and themixture extracted with EtOAc. The organic layers were washed with brine,dried over Na₂SO₄, filtered and condensed. The crude mixture waspurified by chromatography (SiO₂, O-10% MeOH/CH₂Cl₂) to afford the titlecompound (0.015 g, 33%).

¹H NMR (CDCl₃-MeOD [4:2], 500 MHz) δ 7.94 (d, 1H, J=8.0 Hz), 7.33-7.28(m, 2H), 7.03 (t, 1H, J=7.1 Hz), 3.08 (s, 6H). MS (ESI) m/z 229.0 [M+H]⁺([M+H]⁺, C₁₂H₁₃N₄O requires 229.2).

P7C3-S247: ethyl5-tosyl-4,5-dihydro-1H-pyrimido[5,4-b]indole-2-carboxylate

The title compound was synthesized following a reported procedure (Rahtzet al. U.S. Pat. No. 4,564,610 A1).

¹H NMR (CDCl₃, 500 MHz) δ 8.02 (d, 1H, J=8.1 Hz), 7.75 (d, 1H, J=7.4Hz), 7.60 (d, 2H, J=8.4 Hz), 7.34-7.21 (m, 2H), 7.18 (d, 2H, J=8.1 Hz),5.30 (s, 2H), 4.39 (q, 2H, J=7.1 Hz), 2.31 (s, 3H), 1.40 (t, 3H, J=7.1Hz).

P7C3-S248: L-tryptophan

This compound was purchased from SigmaAldrich.

P7C3-S249: L-5-hydroxy-tryptophan

This compound was purchased from SigmaAldrich

P7C3-S248: L-tryptophan methyl ester hydrochloride

This compound was purchased from SigmaAldrich

P7C3-S251:N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-N-(3-methoxyphenyl)methanesulfonamide

P7C3-S251 was synthesized analogously to P7C3-S244 in quantitativeyield.

¹H NMR (CDCl₃, 400 MHz) δ 8.13 (d, J=1.6 Hz, 2H), 7.53 (dd, J=8.8, 1.8Hz, 2H), 7.37-7.30 (m, 1H), 7.26 (d, J=7.7 Hz, 2H), 6.98-6.83 (m, 3H),4.52-4.37 (m, 3H), 4.36-4.17 (m, 2H), 3.82-3.91 (m, 1H), 3.76 (s, 3H),3.71 (s, 1H), 2.93 (s, 3H), 2.28 (d, J=3.7 Hz, 1H). MS (ESI), m/z:calculated 579.97. Found 624.6 (M+HCOO)⁻.

P7C3-S252:N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-N-(3-methoxyphenyl)benzenesulfonamide

P7C3-5252 was synthesized analogously to P7C3-S244 using representativeprocedure 3 and N-(3-methoxyphenyl)benzenesulfonamide and inquantitative yield.

¹H NMR (CDCl₃, 400 MHz) δ 8.13 (d, J=1.9 Hz, 2H), 7.67-7.38 (m, 8H),7.26 (d, J=8.7 Hz, 2H), 6.90 (dd, J=8.4, 2.5 Hz, 1H), 6.73-6.55 (m, 3H),4.50 (dd, J=15.1, 3.4 Hz, 1H), 4.32 (dd, J=15.1, 8.3 Hz, 1H), 4.22 (bs,1H), 3.80-3.65 (m, 5H), 2.32 (d, J=3.9 Hz, 1H). MS (ESI), m/z:calculated 641.98. Found 686.6 (M+HCOO)⁻.

P7C3-S253:N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-N-(3-methoxyphenyl)-2-(trifluoromethyl)benzenesulfonamide

P7C3-S253 was synthesized analogously to P7C3-S244 using representativeprocedure 3 andN-(3-methoxyphenyl)-2-(trifluoromethyl)benzenesulfonamide and inquantitative yield.

¹H NMR (CDCl₃, 400 MHz) 6) 8.11 (d, J=1.9 Hz, 2H), 7.88 (d, J=7.9 Hz,1H), 7.72 (d, J=8.2 Hz, 1H), 7.65 (t, J=7.7 Hz, 1H), 7.59-7.42 (m, 3H),7.36-7.17 (m, 2H), 7.17 (t, J=8.1 Hz, 1H), 6.85-6.62 (m, 3H), 4.46 (dd,J=15.1, 3.6 Hz, 1H), 4.32 (dd, J=15.0, 8.4 Hz, 1H), 4.20 (bs, 1H), 3.93(d, J=6.1 Hz, 1H), 3.75-3.66 (m, 4H), 2.14 (d, J=4.0 Hz, 1H). MS (ESI),m/z: calculated 709.97. Found 754.5 (M+HCOO)⁻.

P7C3-S254:N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-4-methoxy-N-(3-methoxyphenyl)benzenesulfonamide

P7C3-S254 was synthesized analogously to P7C3-S244 using representativeprocedure 3 and 4-methoxy-N-(3-methoxyphenyl)benzenesulfonamide and inquantitative yield.

¹H NMR (CDCl₃, 400 MHz) δ 8.20-8.01 (m, 2H), 7.52 (dd, J=8.6, 1.8 Hz,2H), 7.48 (d, J=8.8 Hz, 2H), 7.23 (m, 3H), 6.91 (d, J=8.9 Hz, 2H),6.89-6.83 (m, 1H), 6.67 (t, J=2.3 Hz, 1H), 6.63-6.57 (m, 1H), 4.53-4.39(m, 1H), 4.37-4.25 (m, 1H), 4.20 (bs, 1H), 3.89 (s, 3H), 3.75 (s, 3H),3.68-3.58 (m, 2H), 2.29 (d, J=4.1 Hz, 1H). MS (ESI), m/z: calculated671.99. Found 716.5 (M+HCOO)⁻.

P7C3-S256:N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-N-(3-methoxyphenyl)methanesulfonamide

P7C3-S256 was synthesized analogously to P7C3-S241 using representativeprocedure 4 with morpho-DAST andN-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-N-(3-methoxyphenyl)methanesulfonamideand in quantitative yield.

¹H NMR (CDCl₃, 400 MHz) δ 8.14 (d, J=2.1 Hz, 2H), 7.55 (dd, J=8.6, 1.9Hz, 2H), 7.33 (t, J=8.0 Hz, 1H), 7.25 (d, J=9.6 Hz, 2H), 7.01-6.82 (m,3H), 4.97 (dm, J_(H-F)=49.2 Hz, 1H), 4.73-4.35 (m, 2H), 4.14-3.98 (m,2H), 3.81 (s, 3H), 2.96 (s, 3H). MS (ESI), m/z: calculated 581.96. Found626.5 (M+HCOO)⁻.

P7C3-S257:N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-N-(3-methoxyphenyl)-2-(trifluoromethyl)benzenesulfonamide

P7C3-S257 was synthesized analogously to P7C3-S241 using representativeprocedure 4 with morpho-DAST andN-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-N-(3-methoxyphenyl)-2-(trifluoromethyl)benzenesulfonamideand in 95% yield.

¹H NMR (CDCl₃, 400 MHz) δ 8.13 (d, J=1.8 Hz, 2H), 7.90 (d, J=7.9 Hz,1H), 7.72 (d, J=8.0 Hz, 1H), 7.65 (t, J=7.8 Hz, 1H), 7.56 (dd, J=8.7,1.9 Hz, 2H), 7.49 (t, J=7.8 Hz, 1H), 7.29 (d, J=8.8 Hz, 2H), 7.16 (t,J=8.1 Hz, 1H), 6.81 (dd, J=8.4, 2.5 Hz, 1H), 6.78-6.64 (m, 2H), 4.93(dm, J_(H-F)=48.1 Hz, 1H), 4.76-4.44 (m, 2H), 4.23 (t, J=14.3 Hz, 1H),4.06 (dd, J=15.2, 6.1 Hz, 1H), 3.71 (s, 3H).

MS (ESI), m/z: calculated 711.97. Found 756.5 (M+HCOO)⁻

P7C3-S258:N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-4-methoxy-N-(3-methoxyphenyl)benzenesulfonamide

P7C3-S258 was synthesized analogously to P7C3-S241 using representativeprocedure 4 with morpho-DAST andN-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-4-methoxy-N-(3-methoxyphenyl)benzenesulfonamideand in quantitative yield.

¹H NMR (CDCl₃, 400 MHz) δ 8.14 (d, J=1.9 Hz, 2H), 7.55 (dd, J=8.8, 1.9Hz, 2H), 7.51 (d, J=8.9 Hz, 2H), 7.26-7.20 (m, 3H), 6.93 (d, J=8.9 Hz,2H), 6.88 (dd, J=8.2, 2.5 Hz, 1H), 6.70 (t, J=2.2 Hz, 1H), 6.64 (dt,J=7.9, 1.4 Hz, 1H), 4.93 (dm, J_(H-F)=48.1, 6.6 Hz, 1H), 4.72 (ddd,J=31.8, 16.0, 2.4 Hz, 1H), 4.52 (td, J=16.9, 16.2, 8.2 Hz, 1H),4.03-3.91 (m, 1H), 3.89 (s, 3H), 3.86-3.76 (m, 1H), 3.75 (s, 3H). MS(ESI), m/z: calculated 673.99. Found 718.6 (M+HCOO)⁻.

P7C3-S262: ethyl 5H-pyrimido[5,4-b]indole-2-carboxylate

The title compound was synthesized following a reported procedure (Rahtzet al. U.S. Pat. No. 4,564,610 A1, incorporated herein by reference).

¹H NMR (CDCl₃, 400 MHz) δ 9.06 (s, 1H), 8.50 (d, 1H, J=8.0 Hz), 7.64(ddd, 1H, J=1.2, 7.1, 8.2 Hz), 7.56 (d, 1H, J=8.3 Hz), 7.36 (ddd, 1H,J=0.9, 7.1, 8.0 Hz), 4.58 (q, 2H, J=7.1 Hz), 1.50 (t, 3H, J=7.1 Hz).

P7C3-S264:N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-1,1,1-trifluoromethanesulfonamide

1-amino-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol (100 mg, 0.2518mmol) and triethylamine (42 μL, 0.3022 mmol) were dissolved in 1.7 mLDCM. The vial was cooled to 0° C. Triflic anhydride (51 μL, 0.3022 mmol)was then added and the solution was left to react overnight. Thereaction mixture was basified with 1M NaOH, and the layers wereseparated. The aqueous layer was washed 3× with DCM and the combinedorganic layers were then acidified using 18% HCl. The mixture wasseparated and the aqueous layer washed 3× with DCM. The combined organiclayers were dried and concentrated to afford crude material as a yellowresidue. This was purified by column chromatography using a gradient 60%DCM/Hex to 90% DCM/MeOH eluent and afforded 8.8 mg (6.6% yield) ofproduct as a white solid. ¹H NMR (500 MHz, CD₃OD) δ 8.23 (d, J=2.1 Hz,1H), 8.21 (d, J=2.3 Hz, 1H), 7.56 (dq, J=8.7, 1.9 Hz, 2H), 7.49 (dd,J=8.7, 5.1 Hz, 2H), 4.40 (ddd, J=15.3, 6.6, 3.6 Hz, 1H), 4.36-4.26 (m,1H), 4.13 (s, 1H), 3.42 (dd, J=13.7, 4.7 Hz, 1H), 3.39-3.32 (m, 1H). MS(ESI) m/z=526.6 ([M−H]⁻, C16H13Br2F3N2O3S requires 527.90.

P7C3-S265: alpidem, also known as6-Chloro-2-(4-chlorophenyl)-N,N-dipropyl-imidazo[1,2-a]pyridine-3-acetamide,6-Chloro-2-(p-chlorophenyl)-N,N-dipropylimidazo[1,2-a]pyridine-3-acetamide

This compound was purchased from SigmaAldrich.

P7C3-S266: TRO 19622, also known as Cholest-4-en-3-one, oxime

This compound was purchased from SigmaAldrich.

P7C3-S267: (+)-a-tocopherol

This compound was purchased from SigmaAldrich.

P7C3-S268: 3-amino-1H-indole-2-carbonitrile

The title compound was made analogously to P7C3-S222.

MS (ESI) m/z: 158.0 [M+H]⁺, C9H7N3 requires 157.1.

P7C3-S269: 8-bromo-1H-pyrimido[5,4-b]indole-2,4(3H, 5H)-dione

The title compound was synthesized following a reported procedure(Reichelt et al. US2011/0021511 A1, incorporated herein by reference).

¹H NMR (d₆-DMSO, 400 MHz) δ 11.97 (s, 1H), 11.57 (s, 1H), 11.15 (s, 1H),8.13 (s, 1H), 7.46 (d, 1H, J=8.9 Hz), 7.36 (d, 1H, J=8.9 Hz). MS (ESI)m/z 281.8 [M+H]⁺ ([M+H]⁺, C₁₀H₇BrN₃O₂ requires 281.0).

P7C3-S270: 8-bromo-2-(dimethylamino)-5H-pyrimido[5,4-b]indol-4-ol

P7C3-S270 was synthesized and isolated in 72% yield analogously toP7C3-S245 except P7C3-S222 was used.

¹H NMR (d₆-DMSO, 400 MHz) δ 11.60 (s, 1H), 11.13 (brs, 1H), 7.97 (s,1H), 7.45 (d, 1H, J=8.8 Hz), 7.36 (d, 1H, J=8.8 Hz), 3.09 (s, 6H). MS(ESI) m/z 307.8 [M+H]⁺ ([M+H]⁺, C₁₂H₁₂BrN₄O requires 308.1).

P7C3-S272:8-bromo-1,3,5-trimethyl-1H-pyrimido[5,4-b]indole-2,4(3H,5H)-dione

NaH (0.087 g, of 60% suspension (in oil), 2.16 mmol) was added to asolution of P7C3-S269 (0.100 g, 0.36 mmol) in dry DMF (1.8 mL) at 0° C.and stirred for 30 min. Then, MeI (168 μL 2.7 mmol) was added dropwiseto the reaction mixture. The reaction was warmed to room temperature andstirred for 3 h. Upon completion, the product was precipitated by theaddition of water, collected by filtration and washed with water. Thetitle compound was isolated as a brown solid (0.115 g, 99%).

¹H NMR (CDCl₃-MeOD [4:2], 500 MHz) δ 7.96 (d, 1H, J=1.7 Hz), 7.39 (dd,1H, J=1.7, 9.0 Hz), 7.20 (d, 1H, J=9.0 Hz), 3.96 (s, 3H), 3.74 (s, 3H),3.30 (s, 3H). MS (ESI) m/z 321.8 [M−H]⁻ ([M−H]⁻, C₁₃H₁₁BrN₃O₂ requires321.1).

P7C3-S275:8-bromo-4-methoxy-N,N,5-trimethyl-5H-pyrimido[5,4-b]indol-2-amine

P7C3-S275 was synthesized and isolated in 24% yield analogously toP7C3-S272 except P7C3-S270 was used.

¹H NMR (CDCl₃, 500 MHz) δ 8.30 (d, 1H, J=1.7 Hz), 7.53 (dd, 1H, J=1.7,8.8 Hz), 7.18 (d, 1H, J=8.8 Hz), 4.10 (s, 3H), 3.93 (s, 3H), 3.25 (s,6H). MS (ESI) m/z 336.0 [M+H]⁺ ([M+H]⁺, C₁₄H₁₆BrN₄O requires 336.2).

P7C3-S276: 3-amino-5-methoxy-1H-indole-2-carbonitrile Step 1. Synthesisof 2-((cyanomethyl)amino)-5-methoxybenzonitrile

Following a reported procedure (Michaelidou, S. S.; Koutentis, P. A.Tetrahedron 2010, 66, 685-688), 2-amino-5-methoxybenzonitrile (Manetsch,R. et al. Chem. Eur. J. 2004, 10, 2487-2506) (0.109 g, 0.74 mmol) wastreated with paraformaldehyde (0.024 mg, 0.81 mmol), potassium cyanide(0.053 g, 0.81 mmol), zinc chloride (0.201 g, 1.473 mmol) and sulfuricacid (1 drop) in acetic acid (2.2 mL) in a sealed tube. The mixture wasthen stirred at 55° C. overnight. The reaction mixture was allowed tocool to room temperature, poured onto ice and made pH neutral withNa₂CO₃. Filtration of the precipitate gave the title compound (0.068 g,50%).

¹H NMR (CDCl₃, 400 MHz) δ 7.11 (dd, 1H, J=2.8, 9.1 Hz), 6.98 (d, 1H,J=2.8 Hz), 6.75 (d, 1H, J=9.1 Hz), 4.15 (s, 2H), 3.74 (s, 3H).

MS (ESI) m/z 188.1 [M+H]⁺ ([M+H]⁺, C₁₀H₁₀N₃O requires 188.2).

Step 2. Synthesis of 3-amino-5-methoxy-1H-indole-2-carbonitrile(P7C3-S276)

P7C3-S276 (Step 2) was synthesized and isolated in quantitative yieldanalogously to P7C3-S222 (Step 2) except2-((cyanomethyl)amino)-5-methoxybenzonitrile was used.

¹H NMR (CDCl₃, 400 MHz) δ 7.11 (d, 1H, J=9.0 Hz), 6.94 (dd, 1H, J=2.4,9.0 Hz), 6.85 (d, 1H, J=2.3 Hz), 3.79 (s, 3H), 2.98 (brs, 2H). MS (ESI)m/z 188.1 [M+H]⁺ ([M+H]⁺, C₁₀H₁₀N₃O requires 188.2).

P7C3-S277:1-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-3-phenylurea

1-amino-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol (100 mg, 0.2518mmol), potassium carbonate (41.8 mg, 0.3022 mmol), and phenyl isocyanate(33 μL, 0.3022 mmol) were dissolved in 5 mL THF. The reaction proceededunder inert atmosphere overnight. The reaction was quenched with waterand the vial allowed to sit for one hour. A thin orange layer wascarefully removed from the bottom of the vial and concentrated to giveyellow residue. This was purified by column chromatography using 5%MeOH/DCM as the eluent to afford 10.1 mg (7.8% yield) of product as atranslucent solid.

¹H NMR (500 MHz, CD₃OD) δ 8.16 (s, 2H), 7.63-7.50 (m, 4H), 7.25-7.15 (m,4H), 7.00 (d, J=7.1 Hz, 1H), 5.16 (t, J=6.1 Hz, 1H), 4.54 (d, J=6.1 Hz,2H), 2.89 (d, J=5.8 Hz, 2H). MS (ESI) m/z=516.0 ([M+H]⁺, C22H19Br2N3O2requires 514.98.

P7C3-S280: 3-bromo-6,9-dimethyl-9H-carbazole

3-bromo-6-methyl-9H-carbazole (100 mg, 0.3844 mmol), NaH (18 mg, 0.4497mmol, 60%), and iodomethane (32 μL, 0.5113 mmol) were dissolved in 0.3mL DMF. The mixture was heated to 60° C. for six hours. The reactionmixture was then quenched with water to give product as a whiteprecipitate. Product was collected via vacuum filtration and rinsed withhexanes. 85.1 mg (83.3% yield) product was collected.

¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, J=2.0 Hz, 1H), 7.83 (dt, J=1.7, 0.9Hz, 1H), 7.52 (dd, J=8.6, 2.0 Hz, 1H), 7.33 (d, J=1.6 Hz, 0H), 7.31 (d,J=1.6 Hz, 1H), 7.30 (d, J=0.7 Hz, 1H), 7.28 (s, OH), 7.26 (s, 1H), 7.23(s, OH), 3.81 (s, 3H), 2.53 (s, 3H). MS (APCI) m/z=274.0 ([M+H]⁺,C₁₄H₁₂BrN requires 273.02.

Additional compounds include:

Pro-Neurogenic Efficacy/Neuroprotection Activity of Various Compounds:

Compounds were administered at a concentration of 10 μM for eachmolecule. After seven days of infusion at a constant rate of 0.5μL/hour, a total of 84 μL of volume will have left the pump (0.00084μMoles) and entered the cerebrospinal fluid. The average volume of abrain from a 12 week old male, C57/B6 mouse in the study is 500 mm³. Themaximal amount of drug was estimated that could potentially be presentin the brain, taking the extreme and unlikely scenario of 100%absorbance of the drug into brain tissue and 0% clearance throughout theseven day infusion period. Under these conditions, at the end of oneweek of infusion each compound would be present at 1.7 μMolarconcentration. Since the actual amount of chemical compound in the brainis likely to be only a fraction of this predicted level, it isreasonable to estimate that compounds were administered at mid tolow-nanomolar concentrations.

During compound infusion, animals were intraperitoneally (IP) injecteddaily with the thymidine analog, bromodeoxyuridine (BrdU), as a means ofscoring the birth and survival of proliferating neural precursor cellsin the hippocampus. Because both social interaction and voluntaryexercise are known to stimulate hippocampal neurogenesis, mice werehoused individually without access to running wheels throughout thescreening period. Following the week-long period of compoundadministration, animals were perfused and sacrificed. Dissected braintissue was fixed, embedded, sectioned, stained with antibodies to BrdU,and evaluated by light microcopy as a means of quantifying neurogenesisand survival of newborn neural precursor cells localized to thesubgranular layer of the dentate gyms on the brain hemispherecontralateral to the side of mini-pump cannulation. Every fifth sectionthroughout the entire rostral-caudal extent of the hippocampus wasanalyzed, and the total number of BrdU+ cells was normalized against themeasured volume of the dentate gyms.

Intracranial infusions of either fibroblast growth factor 2 (FGF-2) orartificial cerebral spinal fluid (aCSF) vehicle via the same, week-longprotocol were employed as positive and negative controls. There was nodifference in the number of BrdU-labeled cells in the dentate gyrusbetween mice subjected to surgical pump implantation and infusion withvehicle, and mice having had no surgery.

Various compounds were tested in vivo for dose-responsive neurotrophicefficacy. The results are shown in Table 1.

TABLE 1 In Vivo Activity SEM: (×10⁻⁰⁶) BrdU+ cells/mm³ (standard errorTest Material dentate gyrus of the mean) Vehicle 14.5 1.08 FGF-2:(fibroblast growth 28.4 2.12 factor 2) P7C3-S76 28.3 1.7 P7C3-S132 22.80.9 P7C3-S133 20.2 1.9 P7C3-S134 19.4 2.1 P7C3-S135 14.2 0.9 P7C3-S13924.9 1.8 P7C3-S140 23.4 3 P7C3-S143 14.5 1.5 P7C3-S144 18.1 1.3P7C3-S145 25 3.1 P7C3-S148 22.6 1.7 P7C3-S149 23.2 1.3 P7C3-S152 26.82.6 P7C3-S158 25 0.8 P7C3-S162 25.2 3.6 P7C3-S163 24.2 2.6 P7C3-S16918.4 1 P7C3-S170 22.4 1.1 P7C3-S171 26.2 2.1 P7C3-S180 25.9 4.6P7C3-S180 18.7 1.6 P7C3-S185 25.1 2.3 P7C3-S189 13.7 1.3 P7C3-S193 15.60.9 P7C3-S199 26.5 3-Feb P7C3-S200 22.1 1.6 P7C3-S201 24.8 2.8 P7C3-S20321.5 2.8 P7C3-S206 29.6 1.4 P7C3-S207 32.4 2.6 P7C3-S209 30 0.4P7C3-S210 21.4 2 P7C3-S211 23 3 P7C3-S212 20.5 2.4 P7C3-S216 25.9 1P7C3-S222 30.1 3.5 P7C3-S223 15.8 0.9 P7C3-S224 20.2 0.8 P7C3-S225 30.42.2 P7C3-S227 25.8 1.5 P7C3-S228 40.3 2.5 P7C3-S229 26.5 3.7 P7C3-S23030.5 1.7 P7C3-S231 26.1 1.8 P7C3-S232 16.8 1.3 P7C3-S235 23.4 2.1P7C3-S236 24.6 2.6 P7C3-S237 23.5 1.3 P7C3-S238 18.8 1.5 P7C3-S239 22.81.4 P7C3-S240 28.5 2.5 P7C3-S241 30.9 1.5 P7C3-S242 21.5 1.7 P7C3-S24423.2 1.9 P7C3-S245 32.4 1.8 P7C3-S246 29 2.4 P7C3-S247 31.1 1 P7C3-S24820.1 1.9 P7C3-S249 34.8 4.1 P7C3-S250 23.7 1.9 P7C3-S251 17.7 1.2P7C3-S252 33.2 1.2 P7C3-S253 28.5 3 P7C3-S254 25.5 0.7 P7C3-S256 31.53.5 P7C3-S257 29.4 2.7 P7C3-S258 29.8 2.3 P7C3-S262 18 1.2 P7C3-S26420.6 0.8 P7C3-S265 29.3 3.6 P7C3-S266 42.3 2.3 P7C3-S267 21.4 1.2P7C3-S268 32.1 1.6 P7C3-S269 35.4 3.7 P7C3-S270 28 4.3 P7C3-S275 20.52.3 P7C3-S276 29.3 3 P7C3-S277 20.3 2.2 P7C3-S280 25.1 1.5

Compounds were evaluated for pro-neurogenic efficacy/neuroprotection ina standard in vivo hippocampal neurogenesis assay at 10 μM concentrationin four 12 week old adult male C57/B16 mice. As shown in Table 1, manycompounds showed high pro-neurogenic and/or neuroprotective activity inthis assay. As such, these compounds can be used to promote neurogenesisand/or reduce neuronal cell death, which are the underlying causes for avariety of neuropsychiatric and neurodegenerative diseases.

Additional methods, assays and animal models for testing pro-neurogenicand/or neuroprotective activity are described in detail in U.S. Pat. No.8,362,277, U.S. Publication No. 2011/0015217, U.S. Publication No.2012/0022096 and U.S. Publication No. 2013/0040977, the entiredisclosures of which are incorporated herein by reference in theirentirety. For example, one of ordinary skill in the art would understandthat the methods and animal models such as in vivo screening forpro-neurogenic compounds, structure activity relationship study, neuronsurvival study, neuronal apoptosis assay, mitochondrial integrity assay,aged rats model, NPAS3-deficient mice, G93A-SOD1 transgenic mice modelof Amyotrophic Lateral Sclerosis, MPTP(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) toxicity model ofParkinson's disease, and R6/2 transgenic mice model of Huntington'sDisease described in these patent and patent application publicationscan be used to further demonstrate the efficacy of the compoundsdescribed herein.

Compound Forms and Salts

The compounds described herein may contain one or more asymmetriccenters and thus occur as racemates and racemic mixtures,enantiomerically enriched mixtures, single enantiomers, individualdiastereomers and diastereomeric mixtures. All such isomeric forms ofthese compounds are expressly included in the presently disclosedembodiments. The compounds of the presently disclosed embodiments mayalso contain linkages (e.g., carbon-carbon bonds, carbon-nitrogen bondssuch as amide bonds) wherein bond rotation is restricted about thatparticular linkage, e.g. restriction resulting from the presence of aring or double bond. Accordingly, all cis/trans and E/Z isomers androtational isomers are expressly included in the presently disclosedembodiments. The compounds of the presently disclosed embodiments mayalso be represented in multiple tautomeric forms, in such instances, thepresently disclosed embodiments expressly include all tautomeric formsof the compounds described herein, even though only a single tautomericform may be represented. All such isomeric forms of such compounds areexpressly included in the presently disclosed embodiments.

Optical isomers can be obtained in pure form by standard proceduresknown to those skilled in the art, and include, but are not limited to,diastereomeric salt formation, kinetic resolution, and asymmetricsynthesis. See, for example, Jacques, et al., Enantiomers, Racemates andResolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al.,Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of CarbonCompounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of ResolvingAgents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of NotreDame Press, Notre Dame, Ind. 1972), each of which is incorporated hereinby reference in their entireties. It is also understood that thepresently disclosed embodiments encompass all possible regioisomers, andmixtures thereof, which can be obtained in pure form by standardseparation procedures known to those skilled in the art, and include,but are not limited to, column chromatography, thin-layerchromatography, and high-performance liquid chromatography.

The compounds of the presently disclosed embodiments include thecompounds themselves, as well as their salts and their prodrugs, ifapplicable. A salt, for example, can be formed between an anion and apositively charged substituent (e.g., amino) on a compound describedherein. Suitable anions include chloride, bromide, iodide, sulfate,nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, andacetate. Likewise, a salt can also be formed between a cation and anegatively charged substituent (e.g., carboxylate) on a compounddescribed herein. Suitable cations include sodium ion, potassium ion,magnesium ion, calcium ion, and an ammonium cation such astetramethylammonium ion. Examples of prodrugs include C₁₋₆ alkyl estersof carboxylic acid groups, which, upon administration to a subject, arecapable of providing active compounds.

Pharmaceutically acceptable salts of the compounds of the presentlydisclosed embodiments include those derived from pharmaceuticallyacceptable inorganic and organic acids and bases. As used herein, theterm “pharmaceutically acceptable salt” refers to a salt formed by theaddition of a pharmaceutically acceptable acid or base to a compounddisclosed herein. As used herein, the phrase “pharmaceuticallyacceptable” refers to a substance that is acceptable for use inpharmaceutical applications from a toxicological perspective and doesnot adversely interact with the active ingredient.

Examples of suitable acid salts include acetate, adipate, alginate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate,camphorate, camphorsulfonate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptanoate, glycolate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate,pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,propionate, salicylate, succinate, sulfate, tartrate, thiocyanate,tosylate and undecanoate. Other acids, such as oxalic, while not inthemselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsof the presently disclosed embodiments and their pharmaceuticallyacceptable acid addition salts. Salts derived from appropriate basesinclude alkali metal (e.g., sodium), alkaline earth metal (e.g.,magnesium), ammonium and N-(alkyl)₄ ⁺ salts. The presently disclosedembodiments also envision the quaternization of any basicnitrogen-containing groups of the compounds disclosed herein. Water oroil-soluble or dispersible products may be obtained by suchquaternization. Salt forms of the compounds of any of the formulaeherein can be amino acid salts of carboxyl groups (e.g. L-arginine,-lysine, -histidine salts).

Lists of suitable salts are found in Remington's PharmaceuticalSciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418;Journal of Pharmaceutical Science, 66, 2 (1977); and “PharmaceuticalSalts: Properties, Selection, and Use A Handbook; Wermuth, C. G. andStahl, P. H. (eds.) Verlag Helvetica Chimica Acta, Zurich, 2002 [ISBN3-906390-26-8] each of which is incorporated herein by reference intheir entireties.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the presently disclosedembodiments.

In addition to salt forms, the presently disclosed embodiments providecompounds which are in a prodrug form. Prodrugs of the compoundsdescribed herein are those compounds that undergo chemical changes underphysiological conditions to provide the compounds of the presentlydisclosed embodiments. Additionally, prodrugs can be converted to thecompounds of the presently disclosed embodiments by chemical orbiochemical methods in an ex vivo environment. For example, prodrugs canbe slowly converted to the compounds of the presently disclosedembodiments when placed in a transdermal patch reservoir with a suitableenzyme or chemical reagent. Prodrugs are often useful because, in somesituations, they may be easier to administer than the parent drug. Theymay, for instance, be more bioavailable by oral administration than theparent drug. The prodrug may also have improved solubility inpharmacological compositions over the parent drug. A wide variety ofprodrug derivatives are known in the art, such as those that rely onhydrolytic cleavage or oxidative activation of the prodrug. An example,without limitation, of a prodrug would be a compound of the presentlydisclosed embodiments which is administered as an ester (the “prodrug”),but then is metabolically hydrolyzed to the carboxylic acid, the activeentity. Additional examples include peptidyl derivatives of a compoundof the presently disclosed embodiments.

The presently disclosed embodiments also include various hydrate andsolvate forms of the compounds.

The compounds of the presently disclosed embodiments may also containunnatural proportions of atomic isotopes at one or more of the atomsthat constitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, for example tritium (³H),iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of thecompounds of the presently disclosed embodiments, whether radioactive ornot, are intended to be encompassed within the scope of the presentlydisclosed embodiments.

Synthesis

The compounds of the presently disclosed embodiments can be convenientlyprepared in accordance with the procedures outlined herein, fromcommercially available starting materials, compounds known in theliterature, or readily prepared intermediates, by employing standardsynthetic methods and procedures known to those skilled in the art.Standard synthetic methods and procedures for the preparation of organicmolecules and functional group transformations and manipulations can bereadily obtained from the relevant scientific literature or fromstandard textbooks in the field. It will be appreciated that wheretypical or preferred process conditions (i.e., reaction temperatures,times, mole ratios of reactants, solvents, pressures, etc.) are given,other process conditions can also be used unless otherwise stated.Optimum reaction conditions may vary with the particular reactants orsolvent used, but such conditions can be determined by one skilled inthe art by routine optimization procedures. Those skilled in the art oforganic synthesis will recognize that the nature and order of thesynthetic steps presented may be varied for the purpose of optimizingthe formation of the compounds described herein.

Synthetic chemistry transformations (including protecting groupmethodologies) useful in synthesizing the compounds described herein areknown in the art and include, for example, those such as described in R.C. Larock, Comprehensive Organic Transformations, 2d. ed., Wiley-VCHPublishers (1999); P. G. M. Wuts and T. W. Greene, Protective Groups inOrganic Synthesis, 4th Ed., John Wiley and Sons (2007); L. Fieser and M.Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wileyand Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents forOrganic Synthesis, John Wiley and Sons (1995), and subsequent editionsthereof.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C), infrared spectroscopy (FT-IR),spectrophotometry (e.g., UV-visible), or mass spectrometry (MS), or bychromatography such as high performance liquid chromatography (HPLC) orthin layer chromatography (TLC).

Preparation of compounds can involve the protection and deprotection ofvarious chemical groups. The need for protection and deprotection, andthe selection of appropriate protecting groups can be readily determinedby one skilled in the art. The chemistry of protecting groups can befound, for example, in Greene, et al., Protective Groups in OrganicSynthesis, 2d. Ed., Wiley & Sons, 1991, which is incorporated herein byreference in its entirety.

The reactions of the processes described herein can be carried out insuitable solvents which can be readily selected by one of skill in theart of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,i.e., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvents.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An examplary method includespreparation of the Mosher's ester or amide derivative of thecorresponding alcohol or amine, respectively. The absolute configurationof the ester or amide is then determined by proton and/or ¹⁹F NMRspectroscopy. An examplary method includes fractional recrystallizationusing a “chiral resolving acid” which is an optically active,salt-forming organic acid. Suitable resolving agents for fractionalrecrystallization methods are, for example, optically active acids, suchas the D and L forms of tartaric acid, diacetyltartaric acid,dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or thevarious optically active camphorsulfonic acids. Resolution of racemicmixtures can also be carried out by elution on a column packed with anoptically active resolving agent (e.g., dinitrobenzoylphenylglycine).Suitable elution solvent compositions can be determined by one skilledin the art.

In certain embodiments, compounds or intermediates thereof maybesynthesized by the following representative scheme.

In the above scheme, “(hetero)aryl” means an aryl or heteroaryl group.R, R², R³, R⁴ and R⁵ represent generic groups or substutients suitablefor the corresponding chemical compound or reaction, as one of ordinaryskill in organic chemistry would understand. For example, R togetherwith the nitrogen it is connected to can form a C4 or C6 ring, which canbe connected to one or more aryl and/or heteroaryl (e.g., optionallysubstituted phenyl, pyridine or pyrimidine). Groups R², R³ and R⁵ may beany group that can form a bond with nitrogen as generally known in theart, such as alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, and/or sulfonyl, each optionally substituted with one ormore halo, hydroxyl, alkoxyl, carboxyl, alkoxycarbonyl, amine, cyano,azide, sulfonyl, alkyl, alkenyl, cycloalkyl, aryl and/or heteroaryl.R⁴.M may be a salt in which R⁴ is a nucleophilic group, such as anegatively charged alkyl group, and M is a positively changed ion suchas a metal ion.

Additional synthesis procedures are described in detail in U.S. Pat. No.8,362,277, U.S. Publication No. 2011/0015217, U.S. Publication No.2012/0022096 and U.S. Publication No. 2013/0040977, the entiredisclosures of which are incorporated herein by reference in theirentirety.

Pharmaceutical Compositions

The term “pharmaceutically acceptable carrier” refers to a carrier oradjuvant that may be administered to a subject (e.g., a patient),together with a compound of the presently disclosed embodiments, andwhich does not destroy the pharmacological activity thereof and isnontoxic when administered in doses sufficient to deliver a therapeuticamount of the compound.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the compositions of the presently disclosed embodiments include,but are not limited to, ion exchangers, alumina, aluminum stearate,lecithin, self-emulsifying drug delivery systems (SEDDS) such asd-α-tocopherol polyethyleneglycol 1000 succinate, surfactants used inpharmaceutical dosage forms such as Tweens or other similar polymericdelivery matrices, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts, or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, orchemically modified derivatives such as hydroxyalkylcyclodextrins,including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilizedderivatives may also be advantageously used to enhance delivery ofcompounds of the formulae described herein.

The compositions for administration can take the form of bulk liquidsolutions or suspensions, or bulk powders. More commonly, however, thecompositions are presented in unit dosage forms to facilitate accuratedosing. The term “unit dosage forms” refers to physically discrete unitssuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical excipient. Typical unit dosage forms includeprefilled, premeasured ampules or syringes of the liquid compositions orpills, tablets, capsules, losenges or the like in the case of solidcompositions. In such compositions, the compound is usually a minorcomponent (from about 0.1 to about 50% by weight or preferably fromabout 1 to about 40% by weight) with the remainder being variousvehicles or carriers and processing aids helpful for forming the desireddosing form.

The amount administered depends on the compound formulation, route ofadministration, etc. and is generally empirically determined in routinetrials, and variations will necessarily occur depending on the target,the host, and the route of administration, etc. Generally, the quantityof active compound in a unit dose of preparation may be varied oradjusted from about 1, 3, 10 or 30 to about 30, 100, 300 or 1000 mg,according to the particular application. In a particular embodiment,unit dosage forms are packaged in a multipack adapted for sequentialuse, such as blisterpack, comprising sheets of at least 6, 9 or 12 unitdosage forms. The actual dosage employed may be varied depending uponthe requirements of the patient and the severity of the condition beingtreated. Determination of the proper dosage for a particular situationis within the skill of the art. Generally, treatment is initiated withsmaller dosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small amounts until the optimumeffect under the circumstances is reached. For convenience, the totaldaily dosage may be divided and administered in portions during the dayif desired.

The following are examples (Formulations 1-4) of capsule formulations.

Capsule Formulations Formulation 1; Formulation 2; Formulation 3;Formulation 4; Capsule Formulations mg/capsule mg/capsule mg/capsulemg/capsule Compound (solid 100 400 400 200 solution) Silicon Dioxide0.625 2.5 3.75 1.875 Magnesium Stearate 0.125 0.5 0.125 0.625 NF2Croscarmellose Sodium 11.000 44.0 40.0 20.0 NF Pluronic F68 NF 6.25025.0 50.0 25.0 Silicon Dioxide NF 0.625 2.5 3.75 1.875 MagnesiumStearate NF 0.125 0.5 1.25 0.625 Total 118.750 475.00 475.00 475.00Capsule Size No. 4 No. 0 No. 0 No. 2

Preparation of Solid Solution

Crystalline compound (e.g., 80 g/batch) and the povidone (NF K29/32 at160 g/batch) are dissolved in methylene chloride (5000 mL). The solutionis dried using a suitable solvent spray dryer and the residue reduced tofine particles by grinding. The powder is then passed through a 30 meshscreen and confirmed to be amorphous by x-ray analysis.

The solid solution, silicon dioxide and magnesium stearate are mixed ina suitable mixer for 10 minutes. The mixture is compacted using asuitable roller compactor and milled using a suitable mill fitted with30 mesh screen. Croscarmellose sodium, Pluronic F68 and silicon dioxideare added to the milled mixture and mixed further for 10 minutes. Apremix is made with magnesium stearate and equal portions of themixture. The premix is added to the remainder of the mixture, mixed for5 minutes and the mixture encapsulated in hard shell gelatin capsuleshells.

Use

In one aspect, methods for treating (e.g., controlling, relieving,ameliorating, alleviating, or slowing the progression of) or methods forpreventing (e.g., delaying the onset of or reducing the risk ofdeveloping) one or more diseases, disorders, or conditions caused by, orassociated with, aberrant (e.g., insufficient) neurogenesis oraccelerated neuron cell death in a subject in need thereof are featured.The methods include administering to the subject an effective amount ofa compound of formula (I) (and/or a compound of any of the otherformulae described herein) or a salt (e.g., a pharmaceuticallyacceptable salt) thereof as defined anywhere herein to the subject.

In another aspect, the use of a compound any of the other describedherein or a salt (e.g., a pharmaceutically acceptable salt) thereof asdefined anywhere herein in the preparation of, or for use as, amedicament for the treatment (e.g., controlling, relieving,ameliorating, alleviating, or slowing the progression of) or prevention(e.g., delaying the onset of or reducing the risk of developing) of oneor more diseases, disorders, or conditions caused by, or associatedwith, aberrant (e.g., insufficient) neurogenesis or exacerbated neuronalcell death is featured.

In some embodiments, the one or more diseases, disorders, or conditionscan include neuropathies, nerve trauma, and neurodegenerative diseases.In some embodiments, the one or more diseases, disorders, or conditionscan be diseases, disorders, or conditions caused by, or associated withaberrant (e.g., insufficient) neurogenesis (e.g., aberrant hippocampalneurogenesis as is believed to occur in neuropsychiatric diseases) oraccelerated death of existing neurons. Examples of the one or moreneuropsychiatric and neurodegenerative diseases include, but are notlimited to, schizophrenia, major depression, bipolar disorder, normalaging, epilepsy, traumatic brain injury, post-traumatic stress disorder,Parkinson's disease, Alzheimer's disease, Down syndrome, spinocerebellarataxia, amyotrophic lateral sclerosis, Huntington's disease, stroke,radiation therapy, chronic stress, and abuse of neuro-active drugs (suchas alcohol, opiates, methamphetamine, phencyclidine, and cocaine),retinal degeneration, spinal cord injury, peripheral nerve injury,physiological weight loss associated with various conditions, andcognitive decline associated with normal aging, radiation therapy, andchemotherapy. The resultant promotion of neurogenesis or survival ofexisting neurons (i.e. a resultant promotion of survival, growth,development, function and/or generation of neurons) may be detecteddirectly, indirectly or inferentially from an improvement in, or anamelioration of one or more symptoms of the disease or disorder causedby or associated with aberrant neurogenesis or survival of existingneurons. Suitable assays which directly or indirectly detect neuralsurvival, growth, development, function and/or generation are known inthe art, including axon regeneration in rat models (e.g. Park et al.,Science. 2008 Nov. 7; 322:963-6), nerve regeneration in a rabbit facialnerve injury models (e.g. Zhang et al., J Transl Med. 2008 Nov. 5;6(1):67); sciatic nerve regeneration in rat models (e.g. Sun et al.,Cell Mol. Neurobiol. 2008 Nov. 6); protection against motor neurondegeneration in mice (e.g. Poesen et al., J. Neurosci. 2008 Oct. 15;28(42):10451-9); rat model of Alzheimer's disease, (e.g. Xuan et al.,Neurosci Lett. 2008 Aug. 8; 440(3):331-5); animal models of depression(e.g. Schmidt et al., Behav Pharmacol. 2007 September; 18(5-6):391-418;Krishnan et al., Nature 2008, 455, 894-902); and/or those exemplifiedherein.

Administration

The compounds and compositions described herein can, for example, beadministered orally, parenterally (e.g., subcutaneously,intracutaneously, intravenously, intramuscularly, intraarticularly,intraarterially, intrasynovially, intrasternally, intrathecally,intralesionally and by intracranial injection or infusion techniques),by inhalation spray, topically, rectally, nasally, buccally, vaginally,via an implanted reservoir, by injection, subdermally,intraperitoneally, transmucosally, or in an ophthalmic preparation, witha dosage ranging from about 0.01 mg/kg to about 1000 mg/kg, (e.g., fromabout 0.01 to about 100 mg/kg, from about 0.1 to about 100 mg/kg, fromabout 1 to about 100 mg/kg, from about 1 to about 10 mg/kg) every 4 to120 hours, or according to the requirements of the particular drug. Theinterrelationship of dosages for animals and humans (based on milligramsper meter squared of body surface) is described by Freireich et al.,Cancer Chemother. Rep. 50, 219 (1966). Body surface area may beapproximately determined from height and weight of the patient. See,e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 537(1970). In certain embodiments, the compositions are administered byoral administration or administration by injection. The methods hereincontemplate administration of an effective amount of compound orcompound composition to achieve the desired or stated effect. Typically,the pharmaceutical compositions of the presently disclosed embodimentswill be administered from about 1 to about 6 times per day oralternatively, as a continuous infusion. Such administration can be usedas a chronic or acute therapy.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of the presently disclosedembodiments may be administered, if necessary. Subsequently, the dosageor frequency of administration, or both, may be reduced, as a functionof the symptoms, to a level at which the improved condition is retainedwhen the symptoms have been alleviated to the desired level. Patientsmay, however, require intermittent treatment on a long-term basis uponany recurrence of disease symptoms.

In some embodiments, the compounds described herein can becoadministered with one or more other therapeutic agents. In certainembodiments, the additional agents may be administered separately, aspart of a multiple dose regimen, from the compounds of the presentlydisclosed embodiments (e.g., sequentially, e.g., on differentoverlapping schedules with the administration of one or more compoundsof formula (I) (including any subgenera or specific compounds thereof)).In other embodiments, these agents may be part of a single dosage form,mixed together with the compounds of the presently disclosed embodimentsin a single composition. In still another embodiment, these agents canbe given as a separate dose that is administered at about the same timethat one or more compounds of formula (I) (including any subgenera orspecific compounds thereof) are administered (e.g., simultaneously withthe administration of one or more compounds of formula (I) (includingany subgenera or specific compounds thereof)). When the compositions ofthe presently disclosed embodiments include a combination of a compoundof the formulae described herein and one or more additional therapeuticor prophylactic agents, both the compound and the additional agent canbe present at dosage levels of between about 1 to 100%, and morepreferably between about 5 to 95% of the dosage normally administered ina monotherapy regimen.

The compositions of the presently disclosed embodiments may contain anyconventional nontoxic pharmaceutically-acceptable carriers, adjuvants orvehicles. In some cases, the pH of the formulation may be adjusted withpharmaceutically acceptable acids, bases or buffers to enhance thestability of the formulated compound or its delivery form.

The compositions may be in the form of a sterile injectable preparation,for example, as a sterile injectable aqueous or oleaginous suspension.This suspension may be formulated according to techniques known in theart using suitable dispersing or wetting agents (for example, Tween 80)and suspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a nontoxic parenterallyacceptable diluent or solvent, for example, as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are mannitol, water, Ringer's solution and isotonic sodiumchloride solution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose, any blandfixed oil may be employed including synthetic mono- or diglycerides.Fatty acids, such as oleic acid and its glyceride derivatives are usefulin the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant,or carboxymethyl cellulose or similar dispersing agents which arecommonly used in the formulation of pharmaceutically acceptable dosageforms such as emulsions and or suspensions. Other commonly usedsurfactants such as Tweens or Spans and/or other similar emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

The compositions of the presently disclosed embodiments may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, emulsions and aqueous suspensions,dispersions and solutions. In the case of tablets for oral use, carrierswhich are commonly used include lactose and corn starch. Lubricatingagents, such as magnesium stearate, are also typically added. For oraladministration in a capsule form, useful diluents include lactose anddried corn starch. When aqueous suspensions and/or emulsions areadministered orally, the active ingredient may be suspended or dissolvedin an oily phase is combined with emulsifying and/or suspending agents.If desired, certain sweetening and/or flavoring and/or coloring agentsmay be added.

The compositions of the presently disclosed embodiments may also beadministered in the form of suppositories for rectal administration.These compositions can be prepared by mixing a compound of the presentlydisclosed embodiments with a suitable non-irritating excipient which issolid at room temperature but liquid at the rectal temperature andtherefore will melt in the rectum to release the active components. Suchmaterials include, but are not limited to, cocoa butter, beeswax andpolyethylene glycols.

Topical administration of the compositions of the presently disclosedembodiments is useful when the desired treatment involves areas ororgans readily accessible by topical application. For applicationtopically to the skin, the composition should be formulated with asuitable ointment containing the active components suspended ordissolved in a carrier. Carriers for topical administration of thecompounds of the presently disclosed embodiments include, but are notlimited to, mineral oil, liquid petroleum, white petroleum, propyleneglycol, polyoxyethylene polyoxypropylene compound, emulsifying wax andwater. Alternatively, the composition can be formulated with a suitablelotion or cream containing the active compound suspended or dissolved ina carrier with suitable emulsifying agents. Suitable carriers include,but are not limited to, mineral oil, sorbitan monostearate, polysorbate60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcoholand water. The compositions of the presently disclosed embodiments mayalso be topically applied to the lower intestinal tract by rectalsuppository formulation or in a suitable enema formulation.

In some embodiments, topical administration of the compounds andcompositions described herein may be presented in the form of anaerosol, a semi-solid pharmaceutical composition, a powder, or asolution. By the term “a semi-solid composition” is meant an ointment,cream, salve, jelly, or other pharmaceutical composition ofsubstantially similar consistency suitable for application to the skin.Examples of semi-solid compositions are given in Chapter 17 of TheTheory and Practice of Industrial Pharmacy, Lachman, Lieberman andKanig, published by Lea and Febiger (1970) and in Remington'sPharmaceutical Sciences, 21st Edition (2005) published by MackPublishing Company, which is incorporated herein by reference in itsentirety.

Topically-transdermal patches are also included in the presentlydisclosed embodiments. Also within the presently disclosed embodimentsis a patch to deliver active chemotherapeutic combinations herein. Apatch includes a material layer (e.g., polymeric, cloth, gauze, bandage)and the compound of the formulae herein as delineated herein. One sideof the material layer can have a protective layer adhered to it toresist passage of the compounds or compositions. The patch canadditionally include an adhesive to hold the patch in place on asubject. An adhesive is a composition, including those of either naturalor synthetic origin, that when contacted with the skin of a subject,temporarily adheres to the skin. It can be water resistant. The adhesivecan be placed on the patch to hold it in contact with the skin of thesubject for an extended period of time. The adhesive can be made of atackiness, or adhesive strength, such that it holds the device in placesubject to incidental contact, however, upon an affirmative act (e.g.,ripping, peeling, or other intentional removal) the adhesive gives wayto the external pressure placed on the device or the adhesive itself,and allows for breaking of the adhesion contact. The adhesive can bepressure sensitive, that is, it can allow for positioning of theadhesive (and the device to be adhered to the skin) against the skin bythe application of pressure (e.g., pushing, rubbing,) on the adhesive ordevice.

The compositions of the presently disclosed embodiments may beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other solubilizing or dispersingagents known in the art.

A composition having the compound of the formulae herein and anadditional agent (e.g., a therapeutic agent) can be administered usingany of the routes of administration described herein. In someembodiments, a composition having the compound of the formulae hereinand an additional agent (e.g., a therapeutic agent) can be administeredusing an implantable device. Implantable devices and related technologyare known in the art and are useful as delivery systems where acontinuous, or timed-release delivery of compounds or compositionsdelineated herein is desired. Additionally, the implantable devicedelivery system is useful for targeting specific points of compound orcomposition delivery (e.g., localized sites, organs). Negrin et al.,Biomaterials, 22(6):563 (2001). Timed-release technology involvingalternate delivery methods can also be used in the presently disclosedembodiments. For example, timed-release formulations based on polymertechnologies, sustained-release techniques and encapsulation techniques(e.g., polymeric, liposomal) can also be used for delivery of thecompounds and compositions delineated herein.

In an aspect, compounds of the presently disclosed embodiments mayinclude those represented by formula (I):

wherein:

-   -   R² and R³, together with C1 and C2, form the optionally        substituted phenyl, pyridine or pyrimidine ring of formulas        (II)-(IV) described below, or are defined as R^(2d) and R^(3d)        of formula (V), respectively;    -   R⁴ is defined as any one of R^(4a)-R^(4d) in formulas (II)-(IV);        and    -   n is 0 or 2.

For example, a compound or pharmaceutically acceptable salt thereof, forpromoting neurogenesis and/or reducing neuronal cell death, can berepresented by formula (II):

-   -   wherein R^(1a) is selected from the group consisting of:        —CH₂—C(O)—Z^(1a) and —CH₂—C(R^(A1))(R^(A2))—CH₂—Z^(2a); and    -   R^(3a) and R^(4a) are each independently selected from the group        consisting of: hydrogen, halo, hydroxyl, C₁₋₃ alkoxyl, cyano,        carboxyl, and formamide;        -   wherein Z^(1a) is selected from the group consisting of:            hydroxyl; C₁₋₆ alkoxyl; amine optionally substituted with 1            or more C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₃₋₁₂ cycloalkyl, C₁₋₁₂            sulfonyl optionally substituted with 1-6 halo, C₆₋₁₂ aryl            sulfonyl optionally substituted with 1-6 halo, C₄₋₁₂            heteroaryl sulfonyl optionally substituted with 1-6 halo,            C₂₋₁₂ carbonyl optionally substituted with 1-6 halo, and/or            C₂₋₁₂-carboxyalkyl optionally substituted with 1-6 halo;            C₂₋₁₂ heterocyclyl; C₆₋₁₂ aryl optionally substituted with 1            or more halo, hydroxyl, C₁₋₆ alkyl and/or C₁₋₆ alkoxyl; and            C₄₋₁₂ heteroaryl optionally substituted with 1 or more halo,            hydroxyl, C₁₋₆ alkyl and/or C₁₋₆ alkoxyl;        -   wherein one of R^(A1) and R^(A2) is hydroxyl, halo, or amine            optionally substituted with 1 or more C₁₋₆ alkyl, C₂₋₆            alkenyl, C₃₋₆ cycloalkyl, C₂₋₆ heterocyclyl, C₆₋₁₂ aryl,            and/or C₄₋₁₂ heteroaryl; and the other of R^(A1) and R^(A2)            is hydrogen;        -   wherein Z^(2a) is selected from the group consisting of:            halo, O(R^(a)), S(R^(b)) and N(R^(c))(R^(d));        -   wherein R^(a) and R^(b) are each independently selected from            the group consisting of: C₁₋₁₂ alkyl; C₂₋₁₂ alkenyl; C₃₋₁₂            cycloalkyl; C₂₋₆ heterocyclyl; C₆₋₁₂ aryl optionally            substituted with 1 or more halo, hydroxyl, C₁₋₆ alkyl and/or            C₁₋₆ alkoxyl; and C₄₋₁₂ heteroaryl optionally substituted            with 1 or more halo, hydroxyl, C₁₋₆ alkyl and/or C₁₋₆            alkoxyl;        -   wherein R^(c) and R^(d) are each independently selected from            the group consisting of: hydrogen; C₁₋₁₂ alkyl; C₂₋₁₂            alkenyl; C₃₋₁₂ cycloalkyl; C₂₋₆ heterocyclyl; C₆₋₁₂ aryl            optionally substituted with 1 or more halo, hydroxyl, C₁₋₆            alkyl and/or C₁₋₆ alkoxyl; and        -   C₄₋₁₂ heteroaryl optionally substituted with 1 or more halo,            hydroxyl, C₁₋₆ alkyl and/or C₁₋₆ alkoxyl; or wherein R^(c)            and R^(d) together with the nitrogen they are attached to            form a C₄₋₁₄ heteroaryl optionally substituted with 1 or            more halo, hydroxyl, C₁₋₆ alkyl and/or C₁₋₆ alkoxyl.

In some embodiments, one or more of the following definitions apply:

-   -   (6) R^(3a) and R^(4a) are both hydrogen or both bromo;    -   (7) Z^(1a) is hydroxyl or amine optionally substituted with 1 or        more C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, and/or C₃₋₁₂ cycloalkyl;    -   (8) one of R^(A1) and R^(A2) is hydroxyl or halo; and the other        of R^(A1) and R^(A2) is hydrogen;    -   (9) Z^(2a) is O(R^(a)) or S(R^(b)); and/or    -   (10) Z^(2a) is N(R^(c))(R^(d)).

For example, R^(1a) may be —CH₂—C(O)—Z^(1a) or—CH₂—C(R^(A1))(R^(A2))—CH₂—Z^(2a).

When R^(1a) is —CH₂—C(O)—Z^(1a), Z^(1a) may be hydroxyl or C₁₋₆ alkoxyl.Z^(1a) may also be amine optionally substituted with 1 or more C₁₋₁₂alkyl, C₂₋₁₂ alkenyl, C₃₋₁₂ cycloalkyl, C₁₋₁₂ sulfonyl optionallysubstituted with 1-6 halo, C₆₋₁₂ aryl sulfonyl optionally substitutedwith 1-6 halo, C₄₋₁₂ heteroaryl sulfonyl optionally substituted with 1-6halo, C₂₋₁₂ carbonyl optionally substituted with 1-6 halo, and/or C₂₋₁₂carboxyalkyl optionally substituted with 1-6 halo. For example, Z^(1a)can be amine optionally substituted with 1 or more C₁₋₁₂ alkyl, C₂₋₁₂alkenyl, and/or C₃₋₁₂ cycloalkyl. Z^(1a) may also be C₂₋₁₂ heterocyclyl;C₆₋₁₂ aryl optionally substituted with 1 or more halo, hydroxyl, C₁₋₆alkyl and/or C₁₋₆ alkoxyl; or C₄₋₁₂ heteroaryl optionally substitutedwith 1 or more halo, hydroxyl, C₁₋₆ alkyl and/or C₁₋₆ alkoxyl.

When R^(1a) is —CH₂—C(R^(A1))(R^(A2))—CH₂—Z^(2a), both of R^(A1) andR^(A2) can be hydrogen. Alternatively, one of R^(A1) and R^(A2) ishydroxyl, halo (e.g., fluoro), or amine optionally substituted with 1 ormore C₁₋₆ alkyl (e.g., methyl), C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₂₋₆heterocyclyl, C₆₋₁₂ aryl, and/or C₄₋₁₂ heteroaryl; and the other ofR^(A1) and R^(A2) is hydrogen. Z^(2a) can be halo, O(R^(a)), S(R^(b)) orN(R^(c))(R^(d)). R^(a) and R^(b) are each common substitutients such as:C₁₋₁₂ alkyl; C₂₋₁₂ alkenyl; C₃₋₁₂ cycloalkyl; C₂₋₆ heterocyclyl; C₆₋₁₂aryl optionally substituted with 1 or more halo, hydroxyl, C₁₋₆ alkyland/or C₁₋₆ alkoxyl; and C₄₋₁₂ heteroaryl optionally substituted with 1or more halo, hydroxyl, C₁₋₆ alkyl and/or C₁₋₆ alkoxyl. R^(c) and R^(d)can both be hydrogen or each common substitutients such as: C₁₋₁₂ alkyl;C₂₋₁₂ alkenyl; C₃₋₁₂ cycloalkyl; C₂₋₆ heterocyclyl; C₆₋₁₂ aryloptionally substituted with 1 or more halo, hydroxyl, C₁₋₆ alkyl and/orC₁₋₆ alkoxyl; and C₄₋₁₂ heteroaryl optionally substituted with 1 or morehalo, hydroxyl, C₁₋₆ alkyl and/or C₁₋₆ alkoxyl. Alternatively, R^(c) andR^(d) together with the nitrogen they are attached to can form a ringstructure, such as a C₄₋₁₄ heteroaryl optionally substituted with 1 ormore halo, hydroxyl, C₁₋₆ alkyl and/or C₁₋₆ alkoxyl.

R^(3a) may be hydrogen, halo (e.g., bromo), hydroxyl, C₁₋₃ alkoxyl(e.g., methoxyl), cyano, carboxyl, or formamide. In certain embodiments,R^(3a) is hydrogen. In some embodiments, R^(3a) is bromo.

R^(4a) may be hydrogen, halo (e.g., bromo), hydroxyl, C₁₋₃ alkoxyl(e.g., methoxyl), cyano, carboxyl, or formamide. In certain embodiments,R^(4a) is hydrogen. In some embodiments, R^(4a) is bromo.

In certain embodiments, the presently disclosed embodiments include acompound or pharmaceutically acceptable salt thereof, for promotingneurogenesis and/or reducing neuronal cell death, the compound havingformula (III):

-   -   wherein R^(1b) is selected from the group consisting of:        hydrogen; C₁₋₆ alkyl optionally substituted with 1 or more halo,        hydroxyl, cyano and/or azide; —CH(R⁵)—C(O)—Z^(1b); and        —CH₂—C(R^(A1))(R^(A2))—CH₂—Z^(2b);        -   wherein R⁵ is hydrogen or C₁₋₃ alkyl;        -   wherein one of R^(A1) and R^(A2) is hydroxyl or halo and the            other is hydrogen;        -   wherein Z^(1b) is selected from the group consisting of:            hydroxyl; C₁₋₆ alkoxyl; and amine optionally substituted            with a hydroxyl, C₁₋₁₂ sulfonyl optionally substituted with            1-6 halo, C₆₋₁₂ aryl sulfonyl optionally substituted with            1-6 halo, C₄₋₁₂ heteroaryl sulfonyl optionally substituted            with 1-6 halo, C₂₋₁₂ carbonyl optionally substituted with            1-6 halo, and/or C₂₋₁₂ carboxyalkyl optionally substituted            with 1-6 halo;        -   wherein Z^(2b) is selected from the group consisting of:            C₁₋₃ alkyl, azide, and N(R⁶)(R⁷);        -   wherein R⁶ and R⁷ are each independently selected from the            group consisting of: hydrogen; carboxamide optionally            substituted with 1 or more C₁₋₆ alkyl, C₆₋₁₂ aryl and/or            C₄₋₁₂ heteroaryl; C₆₋₁₂ aryl optionally substituted with 1            or more halo, hydroxyl, C₁₋₆ alkyl and/or C₁₋₆ alkoxyl;            C₁₋₁₂ sulfonyl optionally substituted with 1-6 halo; C₆₋₁₂            aryl sulfonyl optionally substituted with 1-6 halo; and            C₄₋₁₂ heteroaryl sulfonyl optionally substituted with 1-6            halo; wherein no more than one of R⁶ and R⁷ is hydrogen; and    -   wherein R^(3b) and R^(4b) are each independently selected from        the group consisting of: hydrogen, halo, hydroxyl, C₁₋₃ alkoxyl,        cyano, carboxyl, and formamide.

In some embodiments, one or more of the following definitions apply:

-   -   (5) when R^(1b) is optionally substituted C₁₋₆ alkyl, R^(1b) is        selected from unsubstituted C₁₋₆ alkyl or C₃₋₆ alkyl substituted        with 1 hydroxyl or C₁₋₆ alkyl substituted with 1 cyano;    -   (6) when R^(1b) unsubstituted C₁₋₆ alkyl, R^(1b) is        unsubstituted C₂₋₆ alkyl;    -   (7) when R⁵ is hydrogen, Z^(1b) is amine optionally substituted        with a hydroxyl, C₁₋₁₂ sulfonyl optionally substituted with 1-6        halo, C₆₋₁₂ aryl sulfonyl optionally substituted with 1-6 halo,        C₄₋₁₂ heteroaryl sulfonyl optionally substituted with 1-6 halo,        C₂₋₁₂ carbonyl optionally substituted with 1-6 halo, and/or        C₂₋₁₂ carboxyalkyl optionally substituted with 1-6 halo; and/or    -   (8) Z^(2b) is azide or N(R⁶)(R⁷).

For example, R^(1b) may be hydrogen. R^(1b) may also be C₁₋₆ alkyloptionally substituted with 1 or more halo, hydroxyl, cyano and/orazide, such as unsubstituted C₁₋₆ alkyl (e.g., methyl, ethyl, n-propyl,isopropyl, or tert-butyl) or C₃₋₆ alkyl substituted with 1 hydroxyl(e.g., at the beta-carbon) or C₁₋₆ alkyl substituted with 1 cyano.R^(1b) may also be —CH(R⁵)—C(O)—Z^(1b) or—CH₂—C(R^(A1))(R^(A2))—CH₂—Z^(2b).

R⁵ can be hydrogen or C₁₋₃ alkyl (e.g., methyl). Z^(1b) can be hydroxylor C₁₋₆ alkoxyl. Z^(1b) can also be amine optionally substituted with 1hydroxyl, or amine optionally substituted with C₁₋₁₂ sulfonyl, C₆₋₁₂aryl sulfonyl, C₄₋₁₂ heteroaryl sulfonyl, C₂₋₁₂-carbonyl, orC₂₋₁₂-carboxyalkyl (e.g., —CH₂C(O)OH). The C₁₋₁₂ sulfonyl, C₆₋₁₂ arylsulfonyl, C₄₋₁₂ heteroaryl sulfonyl, C₂₋₁₂ carbonyl, and C₂₋₁₂carboxyalkyl groups can contain one or more common substitutients suchas alkyl, halo, hydroxyl, alkoxyl, aryl and/or heteroaryl.

One of R^(A1) and R^(A2) can be hydroxyl or halo (e.g., fluoro) and theother of R^(A1) and R^(A2) can be hydrogen. Alternatively, both R^(A1)and R^(A2) can be hydrogen. Z^(2b) can be C₁₋₃ alkyl. Z^(2b) can also beazide or N(R⁶)(R⁷). R⁶ and R⁷ can both be hydrogen. Alternatively, onlyone of R⁶ and R⁷ is hydrogen, or none of R⁶ and R⁷ is hydrogen. R⁶ andR⁷ can also be carboxamide optionally substituted with 1 or more C₁₋₆alkyl, C₆₋₁₂ aryl and/or C₄₋₁₂ heteroaryl; C₆₋₁₂ aryl optionallysubstituted with 1 or more halo, hydroxyl, C₁₋₆ alkyl and/or C₁₋₆alkoxyl; C₁₋₁₂ sulfonyl optionally substituted with 1-6 halo; C₆₋₁₂ arylsulfonyl optionally substituted with 1-6 halo; or C₄₋₁₂ heteroarylsulfonyl optionally substituted with 1-6 halo.

R^(3b) may be hydrogen, halo (e.g., bromo), hydroxyl, C₁₋₃ alkoxyl(e.g., methoxyl), cyano, carboxyl, or formamide. In certain embodiments,R^(3b) is hydrogen. In some embodiments, R^(3b) is bromo.

R^(4b) may be hydrogen, halo (e.g., bromo), hydroxyl, C₁₋₃ alkoxyl(e.g., methoxyl), cyano, carboxyl, or formamide. In certain embodiments,R^(4b) is hydrogen. In some embodiments, R^(4b) is bromo.

For example, both R^(3b) and R^(4b) are hydrogen. Both R^(3b) and R^(4b)can be bromo.

In certain embodiments, the presently disclosed embodiments include acompound or pharmaceutically acceptable salt thereof, for promotingneurogenesis and/or reducing neuronal cell death, the compound havingformula (IV):

-   -   wherein:    -   R^(1c) is selected from the group consisting of: hydrogen, C₁₋₆        alkyl, C₁₋₆-carboxyalkyl, C₁₋₁₂ sulfonyl optionally substituted        with 1-6 halo, C₆₋₁₂ aryl sulfonyl optionally substituted with        1-6 halo and C₄₋₁₂ heteroaryl sulfonyl optionally substituted        with 1-6 halo;    -   R^(2c) is selected from the group consisting of: hydrogen;        hydroxyl; cyano; halo; amine optionally substituted with 1 or        more C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, aryl, and/or        heteroaryl; and C₁₋₁₂ alkoxyl;    -   R^(3c) is selected from the group consisting of: carboxyl; C₁₋₆        alkoxycarbonyl; hydroxyl; C₁₋₁₂ alkoxyl; cyano; halo; and amine        optionally substituted with 1 or more C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₃₋₆ cycloalkyl, aryl, and/or heteroaryl;    -   R^(4c) is selected from the group consisting of: hydrogen, halo,        hydroxyl, and C₁₋₃ alkoxyl; and one or both of Q₁ and Q₂ are        nitrogen.

In some embodiments, one or more of the following definitions apply:

-   -   (3) R^(2c) is hydrogen; hydroxyl; or C₁₋₁₂ alkoxyl; and/or    -   (4) R^(3c) is carboxyl; C₁₋₆ alkoxycarbonyl; hydroxyl; or amine        substituted with 1-2 C₁₋₆ alkyl.

For example, R^(1c) can be hydrogen. R^(1c) can also be C₁₋₆ alkyl orC₂₋₆-carboxyalkyl (e.g., —CH₂C(O)OH). R^(1c) can also be C₁₋₁₂ sulfonyloptionally substituted with 1-6 halo or C₆₋₁₂ aryl sulfonyl (e.g.,—S(O)₂Ph) optionally substituted with 1-6 alkyl, substituted alkyl(e.g., CF₃) and/or halo. R^(1c) can also be C₄₋₁₂ heteroaryl sulfonyloptionally substituted with 1-6 alkyl, substituted alkyl (e.g., CF₃)and/or halo.

R^(2c) can be hydrogen or hydroxyl. R^(2c) can also be cyano; halo; oramine optionally substituted with 1 or more C₁₋₆ alkyl, C₂₋₆ alkenyl,C₃₋₆ cycloalkyl, aryl, and/or heteroaryl. R^(2c) can also be C₁₋₁₂alkoxyl.

R^(3c) can be carboxyl or C₁₋₆ alkoxycarbonyl (e.g., —C(O)OCH₃ or—C(O)OCH₂CH₃). R^(3c) can also be hydroxyl. R^(3c) can also be C₁₋₁₂alkoxyl; cyano; or halo (e.g., bromo). R^(3c) can also be amineoptionally substituted with 1 or more C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, aryl, and/or heteroaryl, such as N(CH₃)₂.

R^(4c) can be hydrogen or halo (e.g., bromo). R^(4c) can also behydroxyl or and C₁₋₃ alkoxyl.

Q₁ and Q₂ can both be nitrogen. Alternatively, one of Q₁ and Q₂ isnitrogen and the other of Q₁ and Q₂ is carbon. In some embodiments, whenboth Q₁ and Q₂ are be nitrogen and both R^(2c) and R^(3c) are hydroxyl,the corresponding ring structure is typically represented by:

In certain embodiments, the presently disclosed embodiments include acompound or pharmaceutically acceptable salt thereof, for promotingneurogenesis and/or reducing neuronal cell death, the compound havingformula (V):

-   -   wherein R^(1d) is selected from the group consisting of:        hydrogen and CH₂—C(R^(A1))(R^(A2))—CH₂—N(R⁶)(R⁷);        -   wherein one of R^(A1) and R^(A2) is hydroxyl or halo and the            other is hydrogen; and        -   wherein R⁶ and R⁷ are each independently selected from the            group consisting of: hydrogen; C₆₋₁₂ aryl optionally            substituted with 1 or more halo, hydroxyl, C₁₋₆ alkyl and/or            C₁₋₆ alkoxyl; and C₄₋₁₂ heteroaryl optionally substituted            with 1 or more halo, hydroxyl, C₁₋₆ alkyl and/or C₁₋₆            alkoxyl;    -   wherein R^(2d) is selected from the group consisting of: halo,        hydroxyl, C₁₋₁₂ alkoxyl, cyano, aryl, and heteroaryl;    -   wherein R^(3d) is selected from the group consisting of:        hydrogen and amine optionally substituted with 1 or more C₁₋₆        alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₂₋₆ heterocyclyl, aryl,        and/or heteroaryl; and    -   wherein R^(4d) is selected from the group consisting of:        hydrogen, halo, hydroxyl, and C₁₋₃ alkoxyl.

In some embodiments, R^(2d) is cyano, and/or R^(4d) is hydrogen, bromoor methoxy.

For example, R^(1d) can be hydrogen. R^(1d) can also beCH₂—C(R^(A1))(R^(A2))—CH₂—N(R⁶)(R⁷). One of R^(A1) and R^(A2) can behydroxyl and the other is hydrogen. One of R^(A1) and R^(A2) can be halo(e.g., fluoro) and the other is hydrogen. Alternatively, both R^(A1) andR^(A2) can be hydrogen. R⁶ and R⁷ can both be hydrogen. Alternatively,one or both of R⁶ and R⁷ can be C₆₋₁₂ aryl optionally substituted with 1or more halo, hydroxyl, C₁₋₆ alkyl and/or C₁₋₆ alkoxyl; or C₄₋₁₂heteroaryl optionally substituted with 1 or more halo, hydroxyl, C₁₋₆alkyl and/or C₁₋₆ alkoxyl.

R^(2d) can be halo, hydroxyl, or C₁₋₁₂ alkoxyl. R^(2d) can also becyano. R^(2d) can also be aryl (e.g., C₆₋₁₂) or heteroaryl (e.g.,C₄₋₁₂).

R^(3d) can be hydrogen. R^(3d) can also be amine optionally substitutedwith 1 or more C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₂₋₆heterocyclyl, aryl (e.g., C₆₋₁₂), and/or heteroaryl (e.g., C₄₋₁₂).

R^(4d) can be hydrogen, halo (e.g., bromo), hydroxyl, or C₁₋₃ alkoxyl(e.g., methoxyl).

Compounds or salts thereof having any combinations of the abovedefinitions of the various groups are all included in the presentlydisclosed embodiments.

All publications and patents mentioned herein are hereby incorporated byreference in their entirety as if each individual publication or patentwas specifically and individually indicated to be incorporated byreference.

What is claimed is:
 1. A compound or pharmaceutically acceptable saltthereof, for promoting neurogenesis and/or reducing neuronal cell death,the compound having formula (II):

wherein R^(1a) is selected from the group consisting of:—CH₂—C(O)—Z^(1a) and —CH₂—C(R^(A1))(R^(A2))—CH₂—Z^(2a); R^(3a) andR^(4a) are each independently selected from the group consisting of:hydrogen, halo, hydroxyl, C₁₋₃ alkoxyl, cyano, carboxyl, and formamide;wherein Z^(1a) is selected from the group consisting of: hydroxyl; C₁₋₆alkoxyl; amine optionally substituted with 1 or more C₁₋₁₂ alkyl, C₂₋₁₂alkenyl, C₃₋₁₂ cycloalkyl, C₁₋₁₂ sulfonyl optionally substituted with1-6 halo, C₆₋₁₂ aryl sulfonyl optionally substituted with 1-6 halo,C₄₋₁₂ heteroaryl sulfonyl optionally substituted with 1-6 halo, C₂₋₁₂carbonyl optionally substituted with 1-6 halo, and/or C₂₋₁₂ carboxyalkyloptionally substituted with 1-6 halo; C₂₋₁₂ heterocyclyl; C₆₋₁₂ aryloptionally substituted with 1 or more halo, hydroxyl, C₁₋₆ alkyl and/orC₁₋₆ alkoxyl; and C₄₋₁₂ heteroaryl optionally substituted with 1 or morehalo, hydroxyl, C₁₋₆ alkyl and/or C₁₋₆ alkoxyl; wherein one of R^(A1)and R^(A2) is hydroxyl, halo, or amine optionally substituted with 1 ormore C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₂₋₆ heterocyclyl, C₆₋₁₂aryl, and/or C₄₋₁₂ heteroaryl; and the other of R^(A1) and R^(A2) ishydrogen; wherein Z^(2a) is selected from the group consisting of: halo,O(R^(a)), S(R^(b)) and N(R^(c))(R^(d)); wherein R^(a) and R^(b) are eachindependently selected from the group consisting of: C₁₋₁₂ alkyl; C₂₋₁₂alkenyl; C₃₋₁₂ cycloalkyl; C₂₋₆ heterocyclyl; C₆₋₁₂ aryl optionallysubstituted with 1 or more halo, hydroxyl, C₁₋₆ alkyl and/or C₁₋₆alkoxyl; and C₄₋₁₂ heteroaryl optionally substituted with 1 or morehalo, hydroxyl, C₁₋₆ alkyl and/or C₁₋₆ alkoxyl; wherein R^(c) and R^(d)are each independently selected from the group consisting of: hydrogen;C₁₋₁₂ alkyl; C₂₋₁₂ alkenyl; C₃₋₁₂ cycloalkyl; C₂₋₆ heterocyclyl; C₆₋₁₂aryl optionally substituted with 1 or more halo, hydroxyl, C₁₋₆ alkyland/or C₁₋₆ alkoxyl; and C₄₋₁₂ heteroaryl optionally substituted with 1or more halo, hydroxyl, C₁₋₆ alkyl and/or C₁₋₆ alkoxyl; or wherein R^(c)and R^(d) together with the nitrogen they are attached to form a C₄₋₁₄heteroaryl optionally substituted with 1 or more halo, hydroxyl, C₁₋₆alkyl and/or C₁₋₆ alkoxyl.
 2. The compound or salt of claim 1, whereinR^(3a) and R^(4a) are both hydrogen or both bromo.
 3. The compound orsalt of claim 1, wherein Z^(1a) is hydroxyl or amine optionallysubstituted with 1 or more C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, and/or C₃₋₁₂cycloalkyl.
 4. The compound or salt of claim 1, wherein one of R^(A1)and R^(A2) is hydroxyl or halo; and the other of R^(A1) and R^(A2) ishydrogen.
 5. The compound or salt of claim 1, wherein Z^(2a) is O(R^(a))or S(R^(b)).
 6. The compound or salt of claim 1, wherein Z^(2a) isN(R^(c))(R^(d)).
 7. A compound or pharmaceutically acceptable saltthereof, for promoting neurogenesis and/or reducing neuronal cell death,the compound having formula (III):

wherein R^(1b) is selected from the group consisting of: hydrogen; C₁₋₆alkyl optionally substituted with 1 or more halo, hydroxyl, cyano and/orazide; —CH(R⁵)—C(O)—Z^(1b); and —CH—C(R^(A1))(R^(A2))—CH₂—Z^(2b);wherein R⁵ is hydrogen or C₁₋₃ alkyl; wherein one of R^(A1) and R^(A2)is hydroxyl or halo and the other is hydrogen; wherein Z^(1b) isselected from the group consisting of: hydroxyl; C₁₋₆ alkoxyl; and amineoptionally substituted with a hydroxyl, C₁₋₁₂ sulfonyl optionallysubstituted with 1-6 halo, C₆₋₁₂ aryl sulfonyl optionally substitutedwith 1-6 halo, C₄₋₁₂ heteroaryl sulfonyl optionally substituted with 1-6halo, C₂₋₁₂ carbonyl optionally substituted with 1-6 halo, and/orC₂₋₁₂-carboxyalkyl optionally substituted with 1-6 halo; wherein Z^(2b)is selected from the group consisting of: C₁₋₃ alkyl, azide, andN(R⁶)(R⁷); wherein R⁶ and R⁷ are each independently selected from thegroup consisting of: hydrogen; carboxamide optionally substituted with 1or more C₁₋₆ alkyl, C₆₋₁₂ aryl and/or C₄₋₁₂ heteroaryl; C₆₋₁₂ aryloptionally substituted with 1 or more halo, hydroxyl, C₁₋₆ alkyl and/orC₁₋₆ alkoxyl; C₁₋₁₂ sulfonyl optionally substituted with 1-6 halo; C₆₋₁₂aryl sulfonyl optionally substituted with 1-6 halo; and C₄₋₁₂ heteroarylsulfonyl optionally substituted with 1-6 halo; wherein no more than oneof R⁶ and R⁷ is hydrogen; and wherein R^(3b) and R^(4b) are eachindependently selected from the group consisting of: hydrogen, halo,hydroxyl, C₁₋₃ alkoxyl, cyano, carboxyl, and formamide.
 8. The compoundor salt of claim 7, wherein when R^(1b) is optionally substituted C₁₋₆alkyl, R^(1b) is selected from unsubstituted C₁₋₆ alkyl or C₃₋₆ alkylsubstituted with 1 hydroxyl or C₁₋₆ alkyl substituted with 1 cyano. 9.The compound or salt of claim 8, wherein when R^(1b) unsubstituted C₁₋₆alkyl, R^(1b) is unsubstituted C₂₋₆ alkyl.
 10. The compound or salt ofclaim 7, wherein when R⁵ is hydrogen, Z^(1b) is amine optionallysubstituted with a hydroxyl, C₁₋₁₂ sulfonyl optionally substituted with1-6 halo, C₆₋₁₂ aryl sulfonyl optionally substituted with 1-6 halo,C₄₋₁₂ heteroaryl sulfonyl optionally substituted with 1-6 halo, C₂₋₁₂carbonyl optionally substituted with 1-6 halo, and/or C₂₋₁₂-carboxyalkyloptionally substituted with 1-6 halo.
 11. The compound or salt of claim7, wherein Z^(2b) is azide or N(R⁶)(R⁷).
 12. A compound orpharmaceutically acceptable salt thereof, for promoting neurogenesisand/or reducing neuronal cell death, the compound having formula (IV):

wherein: R^(1c) is selected from the group consisting of: hydrogen, C₁₋₆alkyl, C₁₋₆-carboxyalkyl, C₁₋₁₂ sulfonyl optionally substituted with 1-6halo, C₆₋₁₂ aryl sulfonyl optionally substituted with 1-6 halo and C₄₋₁₂heteroaryl sulfonyl optionally substituted with 1-6 halo; R^(2c) isselected from the group consisting of: hydrogen; hydroxyl; cyano; halo;amine optionally substituted with 1 or more C₁₋₆ alkyl, C₂₋₆ alkenyl,C₃₋₆ cycloalkyl, aryl, and/or heteroaryl; and C₁₋₁₂ alkoxyl; R^(3c) isselected from the group consisting of: carboxyl; C₁₋₆ alkoxycarbonyl;hydroxyl; C₁₋₁₂ alkoxyl; cyano; halo; and amine optionally substitutedwith 1 or more C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, aryl, and/orheteroaryl; R^(4c) is selected from the group consisting of: hydrogen,halo, hydroxyl, and C₁₋₃ alkoxyl; and one or both of Q₁ and Q₂ arenitrogen.
 13. The compound or salt of claim 12, wherein R^(2c) ishydrogen; hydroxyl; or C₁₋₁₂ alkoxyl.
 14. The compound or salt of claim12, wherein R^(3c) is carboxyl; C₁₋₆ alkoxycarbonyl; hydroxyl; or aminesubstituted with 1-2 C₁₋₆ alkyl.
 15. A compound or pharmaceuticallyacceptable salt thereof, for promoting neurogenesis and/or reducingneuronal cell death, the compound having formula (V):

wherein R^(1d) is selected from the group consisting of: hydrogen andCH₂—C(R^(A1))(R^(A2))—CH₂—N(R⁶)(R⁷); wherein one of R^(A1) and R^(A2) ishydroxyl or halo and the other is hydrogen; and wherein R⁶ and R⁷ areeach independently selected from the group consisting of: hydrogen;C₆₋₁₂ aryl optionally substituted with 1 or more halo, hydroxyl, C₁₋₆alkyl and/or C₁₋₆ alkoxyl; and C₄₋₁₂ heteroaryl optionally substitutedwith 1 or more halo, hydroxyl, C₁₋₆ alkyl and/or C₁₋₆ alkoxyl; whereinR^(2d) is selected from the group consisting of: halo, hydroxyl, C₁₋₁₂alkoxyl, cyano, aryl, and heteroaryl; wherein R^(3d) is selected fromthe group consisting of: hydrogen and amine optionally substituted with1 or more C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkyl, C₂₋₆ heterocyclyl,aryl, and/or heteroaryl; and wherein R^(4d) is selected from the groupconsisting of: hydrogen, halo, hydroxyl, and C₁₋₃ alkoxyl.
 16. Thecompound or salt of claim 15, wherein R^(2d) is cyano, and R^(4d) ishydrogen, bromo or methoxy.
 17. A method of treating a disease,disorder, or condition associated with unwanted neuronal cell death orinsufficient neurogenesis, the method comprising administering aneffective amount of the compound or salt of claim
 1. 18. A method oftreating a disease, disorder, or condition associated with unwantedneuronal cell death or insufficient neurogenesis, the method comprisingadministering an effective amount of the compound or salt of claim 7.19. A method of treating a disease, disorder, or condition associatedwith unwanted neuronal cell death or insufficient neurogenesis, themethod comprising administering an effective amount of the compound orsalt of claim
 12. 20. A method of treating a disease, disorder, orcondition associated with unwanted neuronal cell death or insufficientneurogenesis, the method comprising administering an effective amount ofthe compound or salt of claim 15.